„iMinnfnni 


HX641 18355 
RC201  .B17  The  treatment  of  syp 

RECAP 


!      : 


**' 

m 

Columbia  Unttiergi 


\7 


^cJjool  of  Bental  anb  (J^ral  burger? 


jeieference  l^i&rarp 


\ 


% 


Digitized  by  the  Internet  Archive 

in  2010  with  funding  from 

Open  Knowledge  Commons 


http://www.archive.org/details/treatmentofsyphiOObake 


THE  TREATMENT  OF  SYPHILIS 


^  "*T^..  o  ■ 


THE  MACMILLAN  COMPANY 

NEW  YORK  •   BOSTON  •   CHICAGO   •  DALLAS 
ATLANTA   •   SAN  FRANCISCO 

MACMILLAN  &  CO.,  Limited 

LONDON   ■  BOMBAY   •  CALCUTTA 
MELBOURNE 

THE  MACMILLAN  CO.  OF  CANADA,  Ltd. 

TORONTO 


THE  TREATMENT 
OF  SYPHILIS 


BY 
H.  SHERIDAN  BAKETEL,  A.M.,  M.D. 

FELLOW  OF  THE  AMERICAN  COLLEGE  OF  PHYSICIANS;  LT.  COLONEL,  MEDICAL  RESERVE 
CORPS,  UNITED  STATES  ARMY;   PROFESSOR  OF  PREVENTIVE  MEDICINE   AND  HY- 
GIENE AND  LECTURER  ON  GENITO-URINARY  DISEASES  AND  SYPHILIS  IN  THE 
LONG  ISLAND  COLLEGE  HOSPITAL,  BROOKLYN;  ATTENDING  SYPHILOLO- 
GIST  AND  CHIEF   OF  CLINICS,  VOLUNTEER  HOSPITAL,  NEW  YORK; 
GENITO-URINARY  SURGEON  TO  THE  HOUSE  OF  RELIEF  OF  THE 
NEW     YORK     HOSPITAL;    MEDICAL     DIEIECTOR     OF  THE 
H.     A.    METZ     LABORATORIES;  MEMBER    OF    THE 
AMERICAN   UROLOGICAL  ASSOCIATION,  ETC. 


Nrai  f  nrk 

THE  MACMILLAN  COMPANY 

1920 

All  nghts  reserved 


Copyright,  ig2o 
By  the  MACMILLAN  COMPANY 


Set  up  and  electrotyped.     Published  March,  1920. 


TO  MY  BELOVED  FATHER, 
THE  REVEREND  OLIVER  SHERMAN  BAKETEL,  D.D. 

WHOSE  SAINTLY  LIPE  HAS  BEEN  AN  ABHUNG  SOURCE  OF  ADMZRATION,  EN- 
COURAGEBtENT  AND  DEVOTION,  THIS  BOOK  IS  AFFECTIONATELY  DEDICATED 


PREFACE 

To  be  successful  in  the  treatment  of  syphilis,  the  physician 
must  be  the  master  of  intravenous  medication,  for  resultful 
treatment  of  lues  is  dependent  to  a  very  great  extent  on  the  ad- 
ministration of  arsphenamine  or  neoarsphenamine. 

The  existing  textbooks  covering  the  field  of  syphilis,  while 
strong  in  diagnosis  and  prognosis,  are  weak  in  that  part  of  treat- 
ment which  concerns  the  actual  introduction  of  arsenical  prod- 
ucts into  the  system.  They  advise  their  employment  but  fail 
to  give  the  readers  in  minutiae  the  various  steps  by  which  a  suc- 
cessful administration  is  accomplished.  This  fact  is  the  raison 
d'etre  of  this  book. 

It  is  not  a  volume  for  the  skilled  syphilographer,  who  has  a 
technic  which  is  entirely  satisfactory  to  himself,  but  rather  is 
intended  for  those  physicians  who  have  not  heretofore  employed 
the  intravenous  method  of  injection  or  those  whose  acquaintance 
therewith  is  limited.  To  some  the  elaborate  detail  of  description 
as  to  the  preparation  and  injection  of  salvarsan  may  appear 
elementary,  but  in  that  very  fact  Ues  its  strength.  A  wide  ex- 
perience in  the  treatment  of  lues  with  the  arsenicals  and  a  com- 
prehensive knowledge  of  this  field  of  medical  practice  has  dem- 
onstrated that  many  physicians  are  lacking  in  information  as 
to  the  "whys,  wheres  and  hows"  of  intravenous  medication.  It 
is  for  this  great  body  of  medical  men  who  desire  to  treat  intelli- 
gently and  skillfully  the  luetic  cases  which  come  to  their  atten- 
tion that  this  book  has  been  v/ritten. 

The  author  has  drawn  not  only  upon  his  own  knowledge  in  its 
preparation  but  has  also  consulted  the  leading  authorities  on  the 
disease.  Credit  has  been  given  so  far  as  known  and  we  are  in- 
debted to  many  syphilographers  and  professional  friends  for 
advice  and  help. 

Particular  gratitude  is  expressed  to  Dr.  John  A.  Fordyce  and 
to  Dr.  Henry  H.  Morton  for  valuable  suggestions  and  assistance. 


viii  PREFACE 

as  well  as  to  Dr.  Chester  N.  Myers,  U.  S.  Public  Health  Service, 
and  Dr.  A.  E.  Sherndal  for  collaboration  in  the  preparation  of  the 
chemistry  of  the  arsenicals. 

In  carrying  out  the  professional  work  on  which  the  contents 
of  this  book  are  based,  aU  brands  of  arsphenamine  and  neoar- 
sphenamine  have  been  utiHzed,  including  the  German,  American, 
EngUsh  and  Canadian,  but  the  majority  of  the  cases  have  been 
treated  with  salvarsan  and  neosalvarsan  which  seem  to  be  the 
counterparts  of  the  original  products. 

H.  S.  B. 
1 6  Fifth  Avenue,  New  York. 


CONTENTS 

CHAPTER  I 

PAGE 

The  Part  of  the  Wassermann  and  Lange's  Chloride  of  Gold 
Tests  est  the  Diagnosis  and  Control  of  the  Various  Forms  of 
Luetic  Infection , i 

CHAPTER  n 
Antiluetic  Agents lo 

CHAPTER  m 
The  History  and  Chemistry  of  Arsphenamtne ii 

CHAPTER  IV 
The  Chemotherapy  of  Arsenic  Compounds 25 

CHAPTER  V 
Indications,  Contraindications  and  Efficiency  of  Arsphenamine    30 

CHAPTER  VI 
A  Plan  for  Antiluetic  Treatment 37 

CHAPTER  VII 
The  Technic  of  Arsphenamine  Administration 42 

CHAPTER  Vni 
The  Technic  of  Neoarsphenamine  Administration 69 

CHAPTER  IX 
The  Methods  of  Employing  the  Mercurials  and  Iodides 77 

CHAPTER  X 

Reactions  and  Accidents  Following  the  Use  of  Arsphenamine  .  .     88 


X  CONTENTS 

CHAPTER  XI 

PAGE 

The  Wassermann  Reaction  and  the  Effects  of  Treatment 
Thereon 105 

CHAPTER  XII 

The  Treatment  of  Syphilis  of  the  Central  Nervous  System.  ...  114 

CHAPTER  XIII 
The  Treatment  of  Congenital,  Malignant  and  Visceral  Syphilis  139 

CHAPTER  XIV 
Syphilitic  Re-infection 150 

CHAPTER  XV 
The  Cure  of  Syphilis 152 


LIST  OF  ILLUSTRATIONS 

The  Intravenous  Injection  of  Arsphenajune: 

The  apparatus  necessary,  for  articles  on  pages  42-43 Facing  p.  42 

Distilling  Apparatus: 

A  simple  type  for  physicians  who  have  no  gas,  electricity 
or  running  water "     "45 

Distilling  Apparatus: 

A  simple  and  inexpensive  water  still  for  physicians  who 

have  laboratories "     "  46 

Apparatus  for  Holding  Normal  Sodium  Hydrgxid  Solution      "     "  49 
The  Intravenous  Injection  of  Arsphenamtne: 

The  patient,  by  twisting  his  shirt  sleeve  with  the  left  hand, 

makes  a  very  satisfactory  tourniquet "     "52 

The  Intravenous  Injection  of  Arsphenamine: 

The  introduction  of  the  Fordyce  needle  into  the  vein "     "54 

The  Intravenous  Injection  of  Arsphenamine: 

The  needle  having  been  introduced  into  the  vein,  etc "     "  S6 

The  Intravenous  Injection  of  Neoarsphenamene "     "73 

The  Intravenous  Injection  of  Neoarsphenamine: 

Tourniquet  has  been  removed  and  the  concentrated  solu- 
tion is  being  introduced  into  the  vein,  etc "     "74 

The  Intravenous  Injection  of  Neoarsphenamine: 

The  injection  having  been  satisfactorily  completed,  etc "     "76 

Syringe  and  Needle  for  Intramuscular  Mercurial  In- 
jection        "     "  80 

The  Intramuscular  Injection  of  Mercury "     "82 

The  Intramuscular  Injection  of  Mercury: 

After  the  area  has  been  sterilized  with  alcohol  or  iodin,  etc. .        "     "  84 
The  Intramuscular  Injection  of  Mercury: 

After  the  mercury  has  been  slowly  deposited  in  the  mus- 
cles, etc "     "  86 


THE  TREATMENT  OF  SYPHILIS 


THE  TREATMENT  OF  SYPHILIS 


CHAPTER  I 

THE  PART  OF  THE  WASSERMANN  AND  LANGE's  CHLORIDE  OF  GOLD 
TESTS  IN  THE  DMGNOSIS  AND  CONTROL  OE  THE  VARIOUS  FORMS 
OF   LUETIC   INFECTION 

The  Wassermann  Reaction. — It  is  incomprehensible  to  think 
of  treating  a  case  of  syphilis  without  the  frequent  utilization  of 
the  Wassermann  test.  While  this  test  has  been  decried  by  certain 
individuals  and  while  every  careful  observer  will  admit  that 
it  is  not  an  infalHble  test,  it  would  be  out  of  the  question  in  our 
opinion  to  treat  lues  successfully  without  its  employment. 

Throughout  the  pages  of  this  book  we  show  in  the  discussion 
of  various  matters  of  technic  the  occasion  for  employing  the 
Wassermann  reaction,  because  so  far  as  we  are  able  to  determine 
it  is  an  agent  for  the  perfection  of  accuracy  in  diagnosis  which  is 
without  an  equal  in  the  light  of  our  present  knowledge.  Not 
only  does  it  assist  us  diagnostically,  but  it  also  enables  us  to 
arrive  more  definitely  at  a  prognosis. 

It  would  be  out  of  place  in  a  treatise  of  this  sort  to  go  into  the 
technic  of  the  Wassermann  reactions  but,  in  view  of  its  very 
great  importance,  it  seems  advisable  to  discuss  a  few  of  the  terms 
that  are  being  used  in  connection  with  the  Wassermann.  Re- 
produced herewith  are  extracts  written  by  Drs.  0.  S.  Hillman 
and  A.  M.  Burgess  for  Mallory  and  Wright's  excellent  work  on 
Pathological  Technique.  (W.  B.  Saunders  Co.,  Philadelphia, 
1918.) 

Complement  (Alexine). — "This  is  a  substance  which  is  found 
in  all  fresh  sera;  its  activity  is  destroyed  by  exposure  to  heat  at 
55°  or  56°  C.  for  half  an  hour.  Serum  treated  in  this  way  is  said 
to  be  inactivated,  and  can  be  reactivated  by  the  addition  of 


2  THE  TREATMENT  OF  SYPHILIS 

another  serum  containing  active  complement.  The  sera  of 
various  animals  differ  in  their  complementary  activity  and  also 
in  their  fixability,  which  is  another  characteristic  that  is  possessed 
by  complement.  Anti-complementary  action  is  a  property  which 
develops  in  a  serum  on  standing  or  which  may  be  present  to  a 
certain  degree  at  the  time  the  serum  is  drawn.  In  selecting  a 
serum  for  the  Wassermann  reaction  it  is  best  to  choose  one  which 
has  the  greatest  degree  of  activity  and  fixabiHty.  It  has  been 
found  that  guinea-pig  serum  fulfills  these  demands  probably 
better  than  the  serum  of  any  other  species. 

"  Amboceptor. — This  is  a  specific  reaction  product,  which 
may  be  present  in  any  normal  serum,  and  which  can  be  pro- 
duced in  the  serum  of  an  animal  by  repeated  injections  (immuni- 
zation) of  cells  or  substances  (erythrocytes,  serum,  egg-albumin, 
etc.),  for  which  it  has  no  natural  amboceptor.  Amboceptors 
that  are  normally  present  in  serum  are  called  natural  ambocep- 
tors ;  those  which  are  produced  as  the  result  of  artificial  immuniza- 
tion are  called  immune  amboceptors.  Amboceptors  are  classi- 
fied according  to  the  particular  substances  employed  in  their 
production;  for  example,  hemolytic  amboceptors  (also  called 
hemolysins)  are  those  that  are  produced  by  the  injection  of  red 
blood-corpuscles  into  an  animal;  bacteriolytic  amboceptors 
(bacteriolysins)  are  produced  by  the  injection  of  bacterial  ex- 
tracts. An  amboceptor  is  specifically  defined  by  prefixing  the 
term  '  anti '  to  the  name  of  the  particular  species  employed  in  its 
production;  for  instance,  when  sheep's  erythrocytes  are  the 
immunizing  agent,  the  amboceptor  is  designated  as  an  anti- 
sheep  hemolytic  amboceptor. 

"Complement  and  amboceptor  are  the  two  factors  necessary 
in  the  production  of  serum  hemolysis.  This  can  be  demon- 
strated by  a  simple  experiment,  as  follows :  immunize  a  rabbit  to 
human  red  blood-corpuscles  by  means  of  repeated  injections, 
thereby  producing  in  the  rabbit  serum  an  anti-human  hemolytic 
amboceptor.  If  serum  from  such  a  rabbit  is  brought  into  con- 
tact with  a  suspension  of  washed  human  red  blood-corpuscles, 
dissolution  of  the  corpuscles  or  hemolysis  will  take  place;  if,  how- 
ever, the  rabbit  serum  be  heated  to  56°  C.  for  one-half  hour  (in- 


WASSERMANN  AND  LANGE'S  TESTS  3 

activated),  and  then  corpuscles  added,  no  hemolysis  will  occur. 
Finally,  if  normal  human  serum  or  normal  guinea-pig  serum  be 
added  to  the  mixture,  hemolysis  will  go  on  as  before.  These 
three  factors  which  enter  into  this  reaction,  namely,  the  com- 
plement, the  hemolytic  amboceptor,  and  the  red  blood-corpus- 
cles, constitute  what  is  called,  for  the  sake  of  brevity,  the  hemo- 
lytic system. 

"The  function  of  the  amboceptor  in  the  above  reaction  of 
hemolysis  is  to  sensitize  or  prepare  the  erythrocytes  for  the  action 
of  the  complement;  the  latter  than  has  the  power  of  causing 
dissolution  of  the  red  cells,  resulting  in  a  clear  red  fluid.  Neither 
amboceptor  nor  complement  acting  alone  can  produce  this  re- 
sult. For  complete  hemolysis  a  definite  ratio  must  exist  be- 
tween the  various  factors — amboceptor,  complement,  and  ery- 
throcytes. The  requisite  strength  and  proportion  of  these  three 
can  readily  be  estimated  by  titration. 

"  Antigens  and  Antibodies. — Antigens  are  substances  which, 
when  injected  into  a  suitable  animal,  are  capable  of  producing 
in  that  animal  substances  called  antibodies,  the  latter  thus  being 
specific  reaction  products.  Erythrocytes,  bacteria,  and  pro- 
teins are  examples  of  antigens.  Under  antibodies  are  included 
hemolytic  and  bacteriolytic  amboceptors,  agglutinins,  and  pre- 
cipitins. Antibodies  are  also  found  in  the  serum  of  patients 
suffering  from  infections  with  microorganisms.  In  typhoid 
fever,  for  instance,  an  antibody  is  developed  in  the  patient's 
serum  as  a  result  of  the  action  of  the  typhoid  bacillus  upon  the 
immunizing  mechanism  of  the  body. 

"Generally  speaking,  it  may  be  stated  that  antigens  and  anti- 
bodies bear  a  specific  relationship  toward  one  another;  for  in- 
stance, the  hemolytic  amboceptor  produced  by  injecting  a  rabbit 
with  sheep's  red  blood-corpuscles  acts  with  these  corpuscles  only 
and  with  no  others.  The  agglutination  of  t3^hoid  bacUH  by  the 
serum  of  the  typhoid  patient  is  also  an  example  of  this  intimate 
connection  between  antigen  and  antibody;  this  fact  is  made 
practical  use  of  in  the  Widal  reaction  for  the  determination  of 
the  t3^hoid  agglutinin  (antibody).  The  phenomenon  of  precipi- 
tation is  another  instance  of  the  visible  and  direct  action  between 


4  THE  TREATMENT  OF  SYPHILIS 

antigen  and  antibody.  Both  agglutination  and  precipitation 
are  dual  mechanisms  requiring  no  intermediate  agent  to  com- 
plete the  reaction. 

"In  syphilis  an  antibody  is  supposed  to  be  developed  in  the 
patient's  serum,  probably  through  the  action  of  the  treponema 
pallidum.  It  seems  to  be  doubtful,  so  far  as  we  know  at  present, 
whether  the  antibody  in  sj^hiHs  is  actually  specific  or  not.  How- 
ever, from  a  practical  standpoint  it  may  be  said  that  it  is  the 
presence  or  absence  of  this  so-called  syphilitic  antibody  that  we 
seek  to  demonstrate  in  the  serum  diagnosis  of  the  disease. 

"  Complement  Fixation. — As  stated  above,  antigen  and  anti- 
body unite  with  one  another  specifically,  and,  when  united,  ac- 
quire the  property  of  fixing  or  absorbing  complement.  This 
fact  can  be  best  illustrated  by  the  interaction  of  two  sets  of 
antigen-antibody  combination.  Take,  for  example,  a  suspension 
of  typhoid  bacilli  (antigen)  and  bring  it  into  contact  with  typhoid 
serum  (antibody) ;  if  complement  is  now  added,  bacteriolysis  will 
result.  That  complement  has  been  fixed  or  absorbed  by  this 
antigen-antibody  combination  is  evidenced  by  the  fact  that  if 
red  blood-corpuscles  and  their  specific  amboceptor  (another 
antigen-antibody  combination)  be  added  later,  no  hemolysis 
will  occur;  complement,  in  other  words,  is  not  available  for 
hemolysis  on  account  of  being  fixed  by  the  first  antigen-antibody 
combination.  This  is  the  well-known  phenomenon  of  comple- 
ment fixation  or  deviation  of  Bordet  and  Gengou,  upon  which 
the  Wassermann  reaction  and  its  various  modifications  are  based. 
The  so-called  syphilitic  antibody  present  in  a  patient's  serum 
when  brought  into  contact  with  an  antigen  is  capable  of  fixing 
complement.  This  reaction  is  indicated  by  absence  of  hemolysis 
when  the  other  two  factors  of  the  hemolytic  system  are 
added. 

"When  the  reaction  was  first  introduced,  it  was  thought  that 
the  antigen  used  in  the  diagnosis  of  syphilis  was  specific,  as  it 
was  then  made  from  the  liver  of  a  syphilitic  fetus.  This  was  the 
nearest  approach  obtainable  to  actual  extracts  of  the  causative 
agent,  namely,  treponema  pallidum.  It  has  been  conclusively 
proved  that  this  original  antigen  is  not  specific,  as  it  has  been 


WASSERMANN  AND  LANGE'S  TESTS  5 

found  that  extracts  of  normal  livers,  as  well  as  other  organs,  and 
also  certain  lecithin  preparations  will  fix  complement  in  contact 
with  not  only  luetic  sera  but  also  sera  from  patients  infected 
with  leprosy,  yaws,  sleeping-sickness,  and  malaria.  The  variabil- 
ity in  the  statistics  of  different  writers  is  probably  due  to  the 
variety  of  antigens  employed,  and  at  present  this  appears  to  be 
the  principal  limitation  to  the  specificity  of  the  reaction. 

"The  aqueous  extract  of  the  liver  of  a  syphilitic  fetus,  which  is 
used  as  an  antigen  in  the  original  Wassermann  reaction,  is  not 
employed  in  the  following  methods  on  account  of  its  instability, 
and,  incidentally,  on  account  of  the  frequent  difficulty  of  ob- 
taining syphilitic  fetuses.  The  modifications  of  the  original 
test  which  have  been  devised  depend,  for  the  most  part,  on  varia- 
tions in  the  source  of  the  antigen  and  in  the  employment  of  a 
different  hemolytic  system. 

"Probably  the  most  important  modification  is  that  of  Noguchi, 
in  which  an  antihuman  hemolytic  system  is  substituted  for  the 
antisheep  and  the  acetone-insoluble  fraction  of  an  alcoholic 
extract  of  a  normal  organ  (heart,  liver,  or  kidney)  is  used  as 
antigen.  Plain  alcoholic  extracts  of  normal  organs  and  of  livers 
and  spleens  of  syphilitic  fetuses  have  been  used  by  many  workers 
in  the  Wassermann  reaction,  but  at  the  present  time  the  best 
antigen  seems  to  be  an  alcoholic  extract  of  human  heart  muscle 
saturated  with  cholesterin.  On  account  of  its  stability  for  long 
periods,  this  antigen  is  particularly  valuable,  especially  when 
reactions  are  done  at  infrequent  intervals. 

"For  purposes  of  distinction  the  two  following  methods  will  be 
designated  as  the  Wassermann  and  Noguchi  reactions  respec- 
tively, although,  strictly  speaking,  the  name  Wassermann  should 
be  applied  to  the  original  method  of  doing  the  reaction — that 
is,  with  the  aqueous  extract  of  a  liver  of  a  syphilitic  fetus. 

"In  the  Wassermann  reaction  the  patient's  serum  is  inacti- 
vated in  order  to  destroy  the  native  complement,  which  is  pres- 
ent, as  a  rule,  in  an  appreciable  amount.  Complement  of  known 
strength  necessary  for  the  reaction  is  supplied  by  fresh  guinea- 
pig  serum.  In  the  Noguchi  reaction  an  antihuman  hemolytic 
system  is  employed,  as  Noguchi  maintains  that,  owing  to  the 


6  THE  TREATMENT  OF  SYPHILIS 

presence  in  human  serum  of  varying  amounts  of  natural  am- 
boceptor for  sheep's  corpuscles,  many  positive  reactions  are 
rendered  negative  in  the  Wassermaim  test  on  account  of  an  in- 
crease in  the  total  amount  of  amboceptor  present,  thus  disturbing 
the  proper  proportion  between  amboceptor  and  complement 
necessary  for  complete  fixation.  It  is  not  necessary  to  inactivate 
the  patient's  serum  in  the  Noguchi  reaction,  as  the  human  com- 
plement is  only  very  slightly  hemolytic  for  corpuscles  of  the  same 
species,  and  also  because  the  amount  of  complement  present  is 
practically  negligible,  owing  to  the  small  quantity  of  patient's 
serum  used  for  the  test." 

Dr.  Archibald  McNeil,  director  of  laboratories  of  the  National 
Pathological  Laboratories,  differs  from  the  statement  above 
that  cholesterinated  antigen  is  the  best  and  most  reliable  one  to 
employ.  Such  an  antigen  may  at  times  give  positive  results  in 
cases  free  from  luetic  infection,  and,  for  this  reason.  Dr.  McNeil 
believes  that  the  plain  alcoholic  antigen  is  much  safer  and  gives 
results  that  coincide  more  closely  with  clinical  findings  than  does 
the  cholesterinated  antigen.  The  latter  undoubtedly  gives 
positive  results  in  a  number  of  latent  and  treated  cases  of  lues 
in  which  the  plain  alcoholic  extract  antigen  gives  negative  re- 
sults. Dr.  McNeil  feels  it  would  be  better  to  obtain  negative  re- 
sults in  a  positive  case  of  lues  than  positive  results  in  negative 
cases,  especially  as  it  is  generally  understood  by  the  medical 
profession  that  a  negative  result  does  not  exclude  the  possibility 
of  luetic  infection. 

Very  few  practitioners  are  qualified  by  experience  to  make  the 
Wassermann  test,  and  those  who  are  interested  in  it  and  desire 
the  exact  technic  are  referred  to  Mallory  and  Wright's  book. 

Lange's  Colloidal  Gold  Test 

They  will  find  therein  also  a  good  description  of  Lange's  col- 
loidal gold  test  of  the  cerebrospinal  fluid  in  syphilis.  This  test  is 
easily  and  quickly  made.  "It  consists, "  says  Dr.  John  A.  Fordyce 
(Am.  Jour.  Med.  Sci.,  October,  1916)  "  of  a  series  of  color  changes 
which  occur  so  characteristically  and  constantly  that  they  may 


WASSERMANN  AND  LANGE'S  TESTS  7 

be  said  to  be  specific.  It  is  performed  with  ten  dilutions  of  spinal 
fluid  in  geometrical  progression  from  i  to  10  to  i  to  5120.  The 
color  change  depends  on  the  amount  of  colloidal  gold  precipi- 
tated and  varies  from  the  negative  salmon  red  through  red  blue, 
Klac  or  blue,  blue  gray  or  gray,  and  colorless.  These  changes 
may  be  plotted  in  curves  or  are  arbitrarily  expressed  from  zero 
to  five.  A  negative  colloidal  gold  would  show  no  change  and 
would  therefore  be  expressed  as  0000000000.  In  tabes  and  cere- 
brospinal syphiHs  the  reaction  occurs  in  the  lower  dilutions  with 
the  intensity  of  the  change  in  the  third  and  fourth  or  fourth  and 
fifth  tubes.  The  term  'luetic  zone'  or  'luetic  curve'  is  used 
to  describe  this  reaction.  The  reading  would  be  as  follows: 
1 133  200000  or  1223320000.  In  meningitis  of  non-syphilitic 
origin  the  maximum  change  occurs  beyond  the  syphilitic  zone — 
that  is,  in  the  higher  dilutions — while  in  paresis  precipitation  of 
the  colloidal  gold  occurs  regularly  in  the  first  four  to  eight  tubes 
with  decolorization  or  a  turbidity,  and  the  reading  represented 
as  5555431000  or  as  many  fives  as  there  are  decolorized  tubes. 
To  this  zonal  change  Miller  and  Levy  applied  the  term  '  paretic 
curve.'  A  properly  standardized — that  is,  a  neutral  solution  of 
colloidal  gold — shows  either  no  change  at  all  with  a  normal 
spinal  fluid  or  produces  a  slight  variation  with  a  bluish  nuance 
in  the  first  four  or  five  tubes  which  is  negligible.  Some  cases 
may  even  give  a  change  to  a  frank  red  blue  in  the  first  four  tubes, 
so  that  the  reading  would  be  iiiioooooo,  but  with  aU  the  other 
laboratory  findings  negative  it  has  been  shown  this  had  no 
diagnostic  import. 

"It  may  be  said,"  continues  Fordyce,  "  that,  as  a  rule,  there  is 
a  parallelism  between  the  other  positive  findings  in  the  fluid  and 
a  positive  gold  reaction.  The  significance  of  any  one  of  the  in- 
dividual abnormahties  must  be  appreciated  before  a  proper  in- 
terpretation can  be  placed  upon  the  laboratory  findings.  We 
know  that  a  lymphocytosis  alone  is  not  pathognomonic  of  syphilis 
as  a  mild  grade  is  met  with  in  other  affections  of  the  central 
nervous  system  and  that  the  cell  count  cannot  be  relied  upon  to 
differentiate  between  tabes,  cerebrospinal  S3rphilis,  and  general 
paresis,  as  an  equally  high  pleocytosis  may  be  met  with  in  any  of 


8  THE  TREATMENT  OF  SYPHILIS 

these  conditions.  So  too  the  presence  of  globulin  alone  indicates 
organic  disease  of  the  brain  or  cord,  but  does  not  separate 
sjTphilitic  from  non-syphilitic  disease. 

"  More  positive  information  is  derived  from  the  complement- 
fixation  test,  as  a  positive  Wassermann  occurs  only  in  lues.  How- 
ever, his  test  by  itself  does  jiot  supply  a  differential  diagnosis 
as  fixation  to  0.2  c.  c.  or  lower  is  met  with  not  only,  in  paresis  but 
in  some  cases  of  progressive  tabes  3-nd  cerebrospinal  syphilis. 
On  the  other  hand,  with  a  distinctly  syphilitic  process,  as  in 
cerebral  endarteritis,  abortive  or  stationary  forms  of  tabes,  and 
some  types  of  cerebrospinal  syphilis,  the  Wassermann  may  be 
completely  negative.  In  the  last-named  cases  a  supplementary 
gold  test  is  of  value  in  demonstrating  the  luetic  nature  of  the 
condition.  Its  greatest  value  and  by  far  most  prominent  role, 
however,  is  in  distinguishing  between  paresis  and  the  conditions 
which  simulate  it  as  well  as  its  prognostic  significance  in  tabetics 
who  show  no  mental  impairment  but  give  a  paretic  curve.  Since 
the  application  of  the  gold  sol  test  a  number  of  patients  in  whom 
no  cerebral  involvement  was  suspected  have  given  the  curve 
characteristic  of  paresis." 

Clinical  Application  of  the  Wassermann  Reaction 

This  subject  is  so  succinctly  set  forth  by  Dr.  Henry  H.  Morton 
of  Brooklyn  in  his  admirable  book  {Genito-Urinary  Diseases  6° 
Syphilis,  p.  739,  1918,  C.  V.  Mosby  Co.,  St.  Louis),  that  it  is 
presented  here  in  Mo: 

''The  diagnostic  value  of  the  Wassermaim  test  depends  upon 
the  fact  that  the  antibody  contained  in  the  serum  causing  the 
reaction  is  specific,  occurring  only  in  the  serum  of  luetics.  Ex- 
cept in  rare  instances  this  has  been  found  to  be  true.  Positive 
reactions  have  been  obtained  in  frambesia,  relapsing  fever, 
trypanosome  infections,  and  tubercular  leprosy.  It  is  also  found 
positive  after  veronal,  morphin,  scopolamin,  ether  narcosis 
(Wolfsohn),  and  frequently  in  sera  obtained  just  before  or  after 
death.  Therefore,  while  it  is  true  that  a  positive  reaction  is  ob- 
tained in  a  few  diseases  and  conditions  other  than  sjrphilis,  the 


WASSERMANN  AND   LANGE'S  TESTS  9 

differential  diagnosis  between  syphilis  and  those  diseases  should 
not  be  difficult,  at  least  in  this  country,  and  the  reaction  may  be 
said  to  be  practically  specific. 

"A  negative  reaction,  on  the  other  hand,  can  not  be  accepted 
as  proof  that  the  disease  does  not  exist,  as  negative  findings  have 
been  obtained  in  a  small  percentage  of  active  cases  of  syphilis. 
If,  however,  a  negative  reaction  is  repeatedly  obtained  after 
several  trials  made  at  intervals,  it  is  almost  positive  proof  that 
the  disease  is  not  present.  The  reaction  appears  from  two  to 
four  weeks  after  the  appearance  of  the  initial  lesion,  and  persists 
throughout  all  stages  of  the  disease  unless  influenced  by  treat- 
ment. A  positive  reaction  has  been  obtained  forty  or  fifty  years 
after  infection.  Quite  often  a  positive  reaction  may  be  obtained 
before  the  appearance  of  secondary  symptoms.  In  the  active 
stages  of  the  disease  95  per  cent  of  cases  give  a  positive  Wasser- 
mann  reaction  and  at  least  75  per  cent  of  tertiary  cases. 

In  latent  cases  of  the  disease,  while  the  continued  existence 
of  the  spirochetse  renders  the  patients  liable  to  outbreaks  of 
symptoms  at  any  time,  nevertheless,  the  organism  is  often  in  a 
dormant  state,  which  makes  the  appearance  of  symptoms  less 
likely.  In  these  latent  cases  a  positive  reaction  is  obtained  in 
50  per  cent  of  the  cases.  It  is  in  this  class  of  cases  that  the  Was- 
sermann  reaction  is  of  special  value  as  these  patients  are  often 
apparently  healthy  and  may  give  no  history  of  ever  having  had 
the  disease.  Oftentimes  a  negative  reaction  in  these  latent  cases 
may  be  transformed  into  a  positive  reaction  by  the  administra- 
tion of  a  short  course  of  mercury  or  salvarsan." 


CHAPTER  II 


ANTI  LUETIC  AGENTS 


In  the  constitutional  treatment  of  S3^hilis  dependence  is 
placed  mainly  on  three  drugs,  arsenic,  mercury,  and  iodin  in 
the  form  of  the  iodides.    The  preparations  mostly  used  are: 


Arsenic 


Mercury 


Given  by 
Intravenous,  or 
Intramuscular,  or 
Subcutaneous 
Injection  or  by  rectum 


Given 
oraUy 


Arsphenamine 
Neoarsphenamine 


Protiodid 

Bichiorid 

Mercury  with  chalk 

Biniodid 

Calomel 

Blue  Mass 


Iodides 


By 

Fumigation 

Calomel 

Inhalation 

' 

By                                           1 
Inunction 

Oleate — lo  per  cent 
Unguentum  hydrarg)^! 

- 

Bichiorid 

By 

Hypodermic 
Injection  in 
Gluteal 

Soluble 

Succinimid 

Biniodid 

Benzoate 

Muscles 

Insoluble 

Salicylate 
Calomel 

Gray  oil 

Given 

Potassium  ioc 

lid 

By  Hypodermic  Injection 
By  Enema  or 

Sodium  iodid 
Ammonium  i( 

Ddid 

Intravenously 

^  Strontium  ioc 

lid 

CHAPTER  III 

THE  HISTORY  AND   CHEMISTRY   OF   ARSPHENAMINE 

Before  the  knowledge  of  chemotherapy  had  reached  its  present 
stage,  arsenic  compounds  had  been  used  haphazardly  for  the 
cure  or  alleviation  of  syphilis  and  other  protozoal  diseases  for 
many  years,  probably  just  as  long  as  mercury.  At  first  only 
inorganic  arsenic  derivatives  were  known,  but  with  the  exten- 
sion in  the  field  of  preparative  organic  chemistry  which  occurred 
early  in  the  19th  century,  some  organic  combinations  of  arsenic 
became  known  which  were  used  to  some  extent  in  therapy.  The 
recent  development  in  the  use  of  arsenic  compounds  in  medicine 
received  its  original  impetus  in  the  discovery  of  the  curative 
action  of  atoxyl  ^  on  sleeping-sickness.  The  chemical  struc- 
ture of  this  substance,  which  was  obtained  by  the  action  of 
arsenic  acid  on  aniline,  was  first  correctly  explained  in  1907, 
when  Ehrlich  demonstrated  that  it  was  the  sodium  salt  of 
para-amido-phenyl  arsinic  acid.^  The  possibility  of  subject- 
ing this  substance  to  the  chemical  transformations  character- 
istic of  benzol  derivatives  was  thus  opened,  and  from  then 
on  attention  was  chiefly  centered  on  such  aromatic  organic 
arsenic  derivatives  because  of  their  comparatively  low  toxicity 
and  apparent  curative  properties.  In  addition  to  atoxyl,  "Hec- 
tine,"  a  benzene  sulfonate  of  atoxyl,^ 

NaO\ 

0=A<  >-NHSQ2C6H6 

HO/ 

*'Arsacetin,"  an  acetyl  atoxyl,^ 
NaO\ 


O = As<  >-NHC0CH3 

HO/ 


5 


and  "Asiphyl, "  a  mercury  salt,' 

[NH2-C6H4-AsO(OH).0]2Hg 

were  proposed  as  therapeutic  agents. 


12  THE  TREATMENT  OF  SYPHILIS 

Aflanity  between  Certain  Living  Cells  and  Chemical  Sub- 
stances.— The  haphazard  method  of  using  these  compounds 
stopped  with  the  development  of  a  definite  theory  of  specific 
affinity  between  certain  living  cells  and  certain  chemical  sub- 
stances, and  its  practical  application  to  internal  antisepsis  for 
the  cure  of  trypanosome  and  spirochsetal  diseases.  Binz  and 
Schuiz  ^  had  found  that  arsenic  acid  was  reduced  in  animal 
tissues  to  arsenious  acid.  It  had  also  been  noted  that  cacodylic 
acid  was  reduced  in  the  organism.  Ehrlich  concluded  from  this 
that  the  arsenic  compounds  which  had  been  used  hitherto,  and 
which  were  all  derivatives  of  pentavalent  arsenic,  did  not  exercise 
an  action  on  the  parasites  until  after  they  had  been  reduced  by 
the  organism  to  the  trivalent  form. 

Investigation  along  this  hne  led  to  the  greatest  advance 
in  the  preparation  of  therapeutically  valuable  substances.  It 
was  found  that  by  reducing  the  pentavalent  compounds  of 
arsenic  to  the  trivalent  form  an  enormous  increase  in  the  power 
to  destroy  the  parasites  which  cause  disease  was  developed. 
For  example,  para-oxy-phenyl  arsinic  acid  does  not  kill  try- 
panosomes  in  dilutions  as  strong  as  i  or  2%,  whereas  if  reduced 
to  the  corresponding  trivalent  arsenic  compound,  para-oxy- 
phenylarsenoxide,  it  kills  trypanosomes  quickly  in  dilutions  of 
I  to  10  million.^ 

Further  investigation  led  Ehrlich  to  conclusions  in  regard  to 
the  mechanism  of  the  action  of  these  drugs  on  the  parasites, 
which  form  the  basis  of  the  theory  of  arsenic  chemotherapy  as 
at  present  generally  accepted.  According  to  this  theory  the 
parasite  possesses  certain  points  of  attack,  termed  by  Ehrlich 
"  chemoceptors  "  which  have  a  specific  affinity  for  certain  chem- 
ical groups,  of  which  trivalent  arsenic  is  one.  Other  groups,  such 
as  the  amido  (NH2),  the  hydroxyl  (OH),  appear  to  anchor  them- 
selves to  definite  parasites  and  so  exert  on  them  the  specific 
drug  action. 

The  Discovery  of  Salvarsan 

By  a  combination  of  work  in  chemical  synthesis  and  biological 
examination  along  the  lines  of  this  theory,  covering  many  years^ 


HISTORY  AND   CHEMISTRY  OF  ARSPHENAMINE 


13 


Ehrlich  and  his  co-workers  arrived  at  a  substance  which  has  pro- 
duced very  remarkable  therapeutic  results.  It  was  originally  im- 
ported under  the  name  "Salvarsan"  and  its  manufacture  in  this 
country  by  Federal  license  under  the  name  "  Arsphenamine  "  has 
become  an  important  factor  in  the  industry  of  synthetic  drugs. 
Several  milHon  ampules  of  arsphenamine  and  its  compounds 
have  been  manufactured  and  distributed  in  this  country,  and 
the  Government's  campaign  against  venereal  disease  in  which 
arsenicals  of  this  t3Ape  will  play  an  important  part,  has  still 
further  increased  the  necessity  of  production  on  a  large  scale. 

In  the  work  which  led  to  the  preparation  of  salvarsan,  the 
object  sought  after  was  a  substance  which  would  combine 
maximum  toxicity  to  the  disease-producing  parasite  with  min- 
imum toxicity  to  the  organism  which  harbored  the  parasite. 
The  measure  of  the  former  is  the  curative  dose,  of  the  latter  the 
tolerated  dose.  The  success  in  attaining  this  object  may  be 
judged  by  a  comparison  of  the  ratio  of  curative  to  tolerated  dose 
in  some  of  the  better  known  arsenicals:  atoxyl  1:2,  arsacetin  1 13, 
arsenophenyglycine  i  :2,  salvarsan  1 158.^ 

Preparation  of  Arsphenamine 

The  preparation  of  arsphenamine  involves  a  number  of  chem- 
ical processes  in  a  field  which  is  comparatively  complicated  and 
requires  a  large  amount  of  special  knowledge.  It  is  further 
complicated  by  the  necessity  of  extra  precautions  on  account  of 
the  great  susceptibility  of  the  final  product  to  chemical  and 
physical  influences.  A  great  variety  of  methods  for  its  produc- 
tion have  been  proposed  but  as  might  be  expected  the  number 
of  processes  used  for  practical  purposes  is  comparatively  limited. 

The  first  step  in  the  synthesis  of  the  aromatic  organic  arsenic 
compounds  is  the  introduction  of  arsenic  into  the  benzene  nu- 
cleus. The  methods  which  have  been  applied  commercially  for 
this  purpose  are  probably  limited  to  three. 

I.  The  Bechamp  condensation,  melting  arsenic  acid  with 
aniline  to  produce  arsanilic  acid,^  or  with  phenol  to  produce 
para-oxy-phenyl  arsinic  acid.^°     The  best  yields  are  obtained 


14  THE  TREATMENT  OF  SYPHILIS 

in  the  aniline  melt.  The  process  must  be  carefully  regulated  as 
to  proportions  of  reagents  and  temperature,  in  order  to  obtain 
the  best  results.  With  high  temperatures  and  an  excess  of 
aniline,  the  tendency  to  the  formation  of  secondary  arsanilic 
acid  is  increased. 

With  phenol  the  condensation  appears  to  give  less  satisfactory 
yields,  although  as  a  step  in  the  preparation  of  arsphenamine  it 
has  the  advantage  of  leading  more  directly  to  the  goal. 

2.  The  arseniation  of  dimethylaniline  with  arsenic  trichloride, 
leading  to  N-dimethyl  arsanilic  acid.  This  process  appears  to 
be  used  in  connection  with  French  patents  for  the  manufacture 
of  arsphenamine.^^ 

3.  Bart's  reaction,  coupling  diazo  compounds  in  alkaline 
solution  with  sodium  arsenite.  This  method  is  capable  of  very 
wide  appUcation  and  starting  from  para-amido-acetanilide  has 
been  appUed  commercially  to  the  production  of  arsanilic  acid.-^^ 
From  the  arsinic  acids  produced  by  these  methods  a  large  number 
of  derivatives  can  be  obtained,  by  the  usual  chemical  reactions 
on  benzene  compounds.  The  practical  production  on  a  large 
scale  of  some  of  these  requires  considerable  elaboration. 

The  Immediate  Mother  Substance  of  Arsphenamine 

The  immediate  mother  substance  of  arsphenamine  is  3-nitro- 
4-hydroxy-phenylarsinic  acid.  A  large  number  of  procedures  for 
the  preparation  of  this  substance  have  been  proposed.  One  of 
the  methods  generally  used  starts  from  parahydroxy-phenyl 
arsinic  acid,  obtained  by  the  action  of  arsenic  acid  on  phenol, 
or  by  the  diazotization  and  hydrolysis  of  arsanilic  acid.  This 
hydroxy  acid  is  then  nitrated  at  a  low  temperature  to  form  the 
nitrohydroxy  acid.  Another  method  consists  in  combining  ar- 
sanilic with  oxalic  acid,  nitrating  the  resulting  oxalyl  compound, 
subsequent  saponification  and  hydrolysis  v/ith  strong  caustic 
potash  leading  to  the  nitro-hydroxy  acid  which  is  used  for  con- 
version into  arsphenamine. 

The  3-nitro-4-hydroxy-phenyl  arsinic  acid  used  for  the  produc- 
tion of  arsphenamine  can  and  should  be  prepared  in  a  high  state 


HISTORY  AND   CHEMISTRY  OF  ARSPHENAMINE         15 

of  purity.  Arsphenamine  itself  cannot  be  purified,  consequently 
all  possible  extraneous  material  should  be  eliminated,  previous 
to  the  final  step  in  the  manufacture. 

From  3-nitro-4-hydroxy-phenyl  arsinic  acid,  the  process  of  pre- 
paring arsphenamine  consists  in  a  reduction  of  the  nitro  to  an 
amino  group  and  a  partial  reduction  of  the  arsenic  acid  group, 
forming  a  double  bond  between  two  molecules.  The  resulting 
insoluble  arseno  base  is  then  isolated,  converted  into  its  soluble 
dihydrochloride,  isolated  by  suitable  precipitation,  dried  thor- 
oughly in  a  high  vacuum,  and  packed  in  ampules  in  vacuum  or 
inert  gas. 

If  the  reduction  is  carried  too  far,  highly  toxic  arsines  may 
be  formed,  if  the  reduction  is  insufficient  or  improperly  carried 
out,  the  nitro  group  may  be  left  intact,  or  the  arsenoxides  formed. 
Several  methods  for  the  reduction  and  subsequent  treatment 
have  been  proposed.  The  original  scheme  was  a  progressive 
reduction,  first  of  the  nitro  group  by  means  of  sodium  amalgam, 
then  of  the  arsenic  group  by  the  action  of  sulfur  dioxid  in  acid 
solution  with  potassium  iodid  as  a  catalyst.  ^^  Kahn  patented 
a  procedure  involving  a  complete  reduction  to  the  primary 
arsine,  which  was  then  added  to  a  solution  of  the  amino-phenyl- 
arsenoxid  with  which  it  combined  forming  the  arseno  base.^"* 
The  reduction  by  means  of  phosphorous  or  hypophosphorous 
acid  has  also  been  described  ^^  and  the  use  of  zinc  dust,  zinc 
chlorid  and  sulfurous  acid  has  been  subject  of  patents.  ^^ 

For  the  practical  purpose  of  large-scale  production  sodium 
hydrosulfite  has  probably  been  used  exclusively,  and  under 
proper  conditions  has  proven  an  ideal  reagent,  although  it 
introduces  the  necessity  of  removing  certain  impurities  from  the 
crude  arseno  base.  When  this  method  is  used  the  reduction  takes 
place  in  one  stage,  and  the  arseno  base,  being  insoluble  in  the 
medium,  can  be  filtered  directly. 

For  the  preparation  of  the  dihydrochlorid,  a  method  has  been 
patented  for  the  precipitation  of  a  solution  from  hydrochloric 
acid.^^  The  generally  used  procedure  consists  in  dissolving  the 
base  in  methyl-alcoholic  hydrochloric  acid  and  precipitation  of 
the  dihydrochloride  by  means  of  ether,  ^^ 


i6  ■  THE  TREATMENT  OF  SYPHILIS 

In  the  final  steps  of  the  manufacture  of  arsphenamine  it  is 
important  to  exclude  atmospheric  oxygen.  In  the  reduction  by 
sodium  hydrosulfite,  this  is  taken  care  of  by  the  sulfur-dioxid 
formed  by  the  oxidation  of  the  hydrosulfite.  During  the  filtra- 
tion of  the  base,  the  preparation  of  the  dihydrochlorid  and  its 
final  isolation,  air  should  be  replaced  by  carbon  dioxid  or  other 
inert  gas.  To  insure  a  product  of  maximum  stabihty,  it  must  be 
carefully  dried  in  high  vacuum,  and  all  subsequent  operations 
conducted  in  an  atmosphere  of  inert  gas. 

There  appears  to  be  some  doubt  as  to  whether  such  careful 
precautions  are  reaUy  necessary  and  it  is  possible  that  a  pure 
arsphenamine,  particularly  after  moisture  and  solvents  have 
been  removed,  is  a  very  much  more  stable  substance  than  ap- 
pears from  some  of  the  hterature  on  the  subject.  There  is  no 
doubt,  however,  that  in  view  of  the  nature  of  the  material  and 
the  use  to  which  it  is  put,  the  best  method  of  procedure  is  to 
adopt  every  possible  precaution  in  the  manufacture,  even  at 
the  risk  of  overdoing  it. 

Explanatory  Diagrammatic  Outline 

The  large  number  of  proposed  chemical  procedures  for  the 
preparation  of  arsphenamine  and  its  intermediates  is  outlined  in 
the  following  charts,  which  show  the  chemical  relationship  of  the 
various  substances  to  the  final  product,  arsphenamine. 


§ 

Z   2 


Ky^ 


_Z      -  ~  *E 


0*i 


■  ->< 


M 

^       I 


td 


o«i 


r-**    *       4.Z 


L.. 


O^jO 


O'l 


I 

I 
I 
I 


o  e 


■T"T 


^ 


HISTORY  AND   CHEMISTRY  OF  ARSPHENAMINE         19 

It  would  appear  that  every  conceivable  avenue  of  approach 
has  been  utilized  for  the  preparation  of  arsphenamine.  It  is 
probable,  however  that  only  a  few  of  these  proposed  methods 
have  been  applied  to  practical  production  of  the  material.  The 
value  of  any  single  method  can  only  be  judged  by  extensive 
study  and  application  to  the  production  of  material  which  is 
satisfactory  chemically,  therapeutically  and  economically. 

The  considerable  physical  and  chemical  variations  in  different 
brands  of  arsphenamine  as  now  obtainable,  indicate  that  the 
processes  used  by  different  manufacturers  vary  to  some  extent 
either  in  principle  or  method  of  manipulation.  Color  and  solubil- 
ity in  solvents,  particularly  in  methyl  alcohol,  and  the  ease  v/ith 
which  the  material  forms  aqueous  solutions  differ  decidedly  with 
different  brands.  The  arsenic  content  varies  from  about  29  to 
about  33  per  cent.  Since  the  theoretical  arsenic  content  of  pure 
arsphenamine  is  34.2  per  cent,  these  figures  represent  great 
variations  in  purity  and  may  affect  the  dosages  used  in  biological 
tests  and  clinical  practice  by  as  much  as  10  per  cent.  The  im- 
purities which  produce  this  low  arsenic  content  as  far  as  at  present 
known  consist  of  moisture,  various  amounts  of  solvents,  inorganic 
material,  and  sulfur.  These  variations  in  the  product  no  doubt 
have  an  important  bearing  on  variations  in  clinical  results  and 
the  advantages  of  standardizing  the  preparation  are  obvious. 

The  Manufacture  of  Arsphenamine 

At  the  present  time  most  American  manufacturers  produce 
arsphenamine  in  comparatively  small  batches,  of  500  or  1,000 
grams,  and  a  recently  pubhshed  English  monograph  on  organic 
arsenicals  notes  with  apparent  satisfaction  that  batches  of  1,500 
grams  are  being  produced.  For  quantity  production  this  small 
scale  involves  the  employment  of  many  assistants,  working  in 
shifts,  and  an  obvious  possibility  of  insufficient  control  resulting 
in  a  lack  of  uniformity  in  the  product.  By  calling  to  aid  the 
mechanical  means  well  known  to  the  chemical  engineer,  so  as  to 
insure  absolute  and  constant  control  throughout  the  process,,  it 
has  been  found  possible  to  produce  salvarsan  in  batches  of  over 


20  THE  TREATMENT  OF  SYPHILIS 

7,000  ampules  at  a  time.  Careful  comparisons  have  shown  that 
the  material  manufactured  on  this  scale  is  as  good  or  better  than 
can  be  obtained  from  small  laboratory  batches  in  which  identical 
raw  materials  are  used.  The  capacity  of  a  plant  operating  on 
this  basis  is  about  14,000  ampules  of  0.6  gram  every  14  to  16 
hours.  This  large-scale  production  also  has  the  advantage  of 
insuring  the  absolute  identity  of  a  large  amount  of  material, 
from  which  data  can  be  obtained  in  regard  to  the  influence  of 
technic  and  personal  factors  on  the  results  obtained  from  the 
administration.  At  the  same  time  it  gives  the  practitioner 
complete  assurance  as  to  the  uniformity  of  a  product  should  he 
desire  to  use  many  doses  of  one  batch  on  a  series  of  patients  for 
purposes  of  comparative  study.  The  product  is  uniform  chem- 
ically, toxicologically  and  therapeutically.  It  is  identical  in 
every  respect  with  the  original  preparation  upon  which  the 
therapeutic  reputation  of  the  drug  was  established.  It  is  tol- 
erated by  test  animals  in  doses  of  120  mg.  and  higher  pro  kilo 
body  weight  which  represents  a  very  low  toxicity  as  compared 
with  other  drugs  used  in  a  similar  manner. 

A  criticism  of  arsphenamine  may  be  made  on  the  ground  of 
inconvenience  in  administration.  The  product  occurs  in  the 
form  of  its  dihydrochloride,  which  should  be  readily  soluble  in 
water  of  ordinary  temperature.  This  solution  is  not  suitable  for 
injection,  however,  until  the  hydrochloric  acid  has  been  neu- 
tralized and  the  arsphenamine  then  further  converted  into  its 
di-sodium  salt.  The  addition  of  the  improper  amount  of  alkali 
for  this  purpose,  either  too  much  or  too  little,  produces  solutions 
which  may  give  trouble  in  injection.  If  the  arsphenamine 
requires  hot  or  boiling  v/ater  to  form  the  solution,  the  preliminary 
preparation  of  the  intravenous  solution  becomes  still  more  com- 
plicated, and  more  possibilities  of  affecting  the  proper  action  of 
the  drug  are  introduced. 

The  Evolution  of  Neoarsphenamine 

With  the  idea  of  simplifying  the  technic  of  administration, 
modifications  prepared  from  arsphenamine  have  been  intro- 
duced which  dissolve  readily  in  water,  forming  solutions  wliich 


HISTORY  AND   CHEMISTRY  OF  ARSPHENAMINE         21 

are  ready  for  injection  without  further  manipulation.  Of  these, 
neoarsphenamine  is  coming  largely  into  favor,  since  in  addition 
to  its  convenient  administration  it  is  also  less  toxic  than  arsphen- 
amine.  This  substance  is  prepared  from  arsphenamine  by  com- 
bination with  sodium  formaldehyde  sulfoxylate.  It  occurs  in  the 
form  of  its  yellow  sodium  salt,  readily  soluble  in  water  with 
slightly  alkaline  reaction.  This  product  is  being  manufactured 
on  a  large  scale  in  the  United  States  and  a  very  extended  use  in 
clinical  practice  has  given  satisfactory  results. 

The  dry  sodium  salt  of  arsphenamine  has  also  been  proposed 
as  a  more  convenient  form  for  administration.  This  dissolves 
readily  in  water  forming  a  solution  which  corresponds  exactly  to 
that  obtained  in  the  preparation  of  a  properly  alkalinized  ar- 
sphenamine solution.  It  has  been  manufactured  in  this  country, 
but  does  not  appear  to  have  come  into  any  extended  use. 

A  number  of  other  arsenicals  have  been  proposed  as  substitutes 
for  or  as  improvements  on  arsphenamine.  Since  arsphenamine 
is  a  patented  product  and  can  only  be  manufactured  under 
license,  it  is  obvious  that  many  attempts  to  introduce  competitive 
products  will  be  made.  So  far,  no  other  arsenical  has  shown 
advantages  which  would  enable  it  to  replace  or  compete  with 
arsphenamine  to  any  marked  degree. 

The  Precursors  of  Arsphenamine 

During  the  work  which  culminated  in  the  preparation  of  ars- 
phenamine, a  very  large  number  of  other  arsenicals  were  syn- 
thesized and  studied,  some  of  which  were  for  a  time  used  in 
therapy.  They  may  be  considered  as  the  precursors  of  arsphe- 
namine, and  the  results  of  their  use  indicated  the  lines  along 
which  improvements  might  be  effected.  As  already  noted, 
atoxyl  was  the  first  of  the  extensively  used  aromatic  organic 
arsenicals.  This  was  replaced  later  by  its  acetic  acid  derivative 
under  the  name  of  arsacetine. 

After  EhrHch  took  up  the  study  of  these  arsenicals  and  dis- 
covered the  decided  increase  in  trypanocidal  efficiency  caused  by 
their  reduction   to   the   trivalent   arseno   compounds,   phenyl- 


22  THE  TREATMENT  OF  SYPHILIS 

glycine-arsinic  acid  was  introduced  as  No.  418  in  his  experi- 
mental series.  Its  sodium  salt,  under  the  name  "spirarsyl"  con- 
stituted an  important  advance  over  atoxyl  and  its  immediate 
derivatives,  and  was  the  most  successful  remedy  among  the 
arsenicals  which  preceded  salvarsan. 

It  was  later  replaced  by  salvarsan,  No.  606,  of  Ehrhch's  series, 
which  represents  the  culminating  point  of  this  line  of  research. 
Attempts  to  simpHfy  its  use  in  therapeutics  led  to  the  introduc- 
tion of  neosalvarsan  and  salvarsan  sodium  which  have  already 
been  described.    The  former  is  numbered  914  in  Ehrhch's  series. 

Working  along  the  same  line  and  with  a  similar  object  in  view, 
Mouneyrat  prepared  a  phosphamic  acid  derivative  of  arsphen- 
amine  which  was  marketed  under  the  name  "Galyl"  No.  11 16, 
and  subsequently  a  complex  disulfonamide  of  arsphenamine 
appeared  under  the  name  "Ludyl,"  No.  1151  of  Mouneyrat's 
series.  These  preparations  both  belong  to  the  neoarsphena- 
mine  type  of  arsphenamine  derivatives,  intended  to  produce 
neutral  or  feebly  alkaline  solutions  ready  for  injection  without 
preUminary  manipulation. 

Other  Arsphenamine  Derivatives 

Another  type  of  arsphenamine  derivatives  which  have  received 
considerable  attention  are  the  co-ordination  compounds  with 
various  metals.  This  interaction,  discovered  during  Ehrhch's 
researches  on  salvarsan,  appears  to  be  a  general  one  with  organic 
arsenical  compounds,  although  on  account  of  their  therapeutic 
importance  it  is  chiefly  the  co-ordination  compounds  of  arsphena- 
mine which  have  been  studied. 

Danysz  prepared  co-ordination  compounds  of  arsphenamine 
with  silver  salts,  and  introduced  "Luargol"  in  which  the  action 
of  the  drug  is  reinforced  by  silver  bromide  and  antimony  oxide. 
A  large  number  of  other  co-ordination  compounds  of  arsphena- 
mine and  neoarsphenamine  have  been  studied,  in  which  salts 
of  mercury,  silver,  gold,  copper  and  platinum  are  in  combination, 
but  the  preparations  mentioned  above  are  the  only  ones  which 
have  been  used  therapeutically  to  any  extent.    The  same  applies 


HISTORY  AND   CHEMISTRY  OF  ARSPHENAMINE         23 

to  other  modifications  of  the  molecule,  in  which  the  various  char- 
acteristic groups  have  been  substituted  or  rearranged  with  a  view 
to  modifying  or  improving  the  therapeutic  action. 

It  is  not  many  years  ago  that  the  chemistry  of  the  organic 
arsenic  compounds  occupied  only  a  very  modest  place  in  chemical 
literature,  but  in  recent  years,  the  interest  in  their  therapeutic 
application  has  developed  a  voluminous  record  of  research  and 
experiment  along  these  lines,  and  several  monographs  on  or- 
ganic arsenicals  have  been  published.  The  chemical  structure  of 
the  arsenicals  mentioned  above  is  shown  in  the  following  cut, 
and  also  some  of  the  modifications  of  arsphenamine  which  have 
been  patented  with  the  object  of  introduction  as  arsphenamine 
substitutes.  They  will  indicate  some  of  the  lines  along  which 
attempts  are  being  made  to  improve  or  replace  the  products 
which  are  now  in  use. 

Spirarsyl — sodium  arsenophenylglycinate 

No.  418  in  Ehrich's  series 
NHCHaCOONa       NHCH2C00Na 
C6H4  — As  =  As  — C6H4 
Galyl — dihydroxy-arsenobenzene-phosphamic  acid 

No.  1 1 16  of  Mouneyrat's  series 

HO.CeHg— As  =  As— CeHg.OH 

NH^-_^,,^NH 
P.O(OH) 

LuDYL — benzene-disulphamino-bis-amino-dihydroxy  arseno  benzene 

No.  1151  of  Mouneyrat's  series 

/SO2NH  CeHaCOH)— As  =  As— C6H3(OH)(NH2) 
C6H4^  SO2NH  CgHsCOH)— As  =  As— CeHaCOH) (NH2) 


24  THE  TREATMENT  OF  SYPHILIS 

LuARGOL. — diamino-dihydroxy   arseno   benzene-silver-bromide-antimonyl- 
sulfate. 

No.  I02  of  Danysz  series 
[(NH2)(OH)C6H3— As  =  As— C6H3(OH)(NH2)]2  Ag  Br.  SbO.  (H2S04)2 

Typical  co-ordination  compound;  AS Me    X 

Me        denotes    metal  || 

X  "        halogen  AS Me    X 

BIBLIOGRAPHY 

1.  Thomas  and  Breinl,  about  1902. 

2.  EhrHch  and  Bertheim,  Ber.  (1907)  40-3292. 

3.  Balzer  and  Moimeyxat,  Progres  Medical  (1909,  No.  27);  French  Patent 

401586  (1908). 

4.  U.  S.  P.  907016  (1908). 

5.  May,  Baker  and  Bates,  Eng.  Pat.  8959  and  24428  (1908);  Fr.  Pat. 
396i92;D.  R.  P.  237787. 

6.  Ber.  12,  2200;  14,  2400. 

7.  Ber.  42,  28. 

8.  EhrHch  and  Hata,  Experimental  Chemotherapy  of  SpiriUoses,  London 

1911. 

9.  O.  and  K.  Adler,  Ber.  41,  932  (1908);  Kober,  J.  A.  C.  S.  (1919)  451. 

10.  Mouneyrat,  Eng.  Pat.  3087  (1908). 
Conant,  J.  A.  C.  S.  (1919)  431. 

11.  Poulenc  and  Oechslin,  Fr.  Pat.  449373,  451078,  474056. 

12.  Bart,  D.  R.  P.  250264,  Eng.  Pat.  568  (1911). 

13.  EhrHch  and  Bertheim,  U.  S.  P.  986148. 
Benda   and  "        Ber.  41,  1657  (1908). 
EhrHch  and          "        Ber.  45,  761  (1912). 

14.  D.  R.  P.  251571,  254187. 

15.  D.  R.  P.  271894,  206456. 

16.  Poulenc,  Eng.  Pat.  21421  (1914). 

17.  See  15,  and  also  D.  R.  P.  216270,  235430,  269886,  269887, 
Kober  J.  A.  C.  S.  (1919)  442. 

18.  Morgan,  Organic  Compounds  of  Arsenic  and  Antimony  (1918),  p.  226. 

19.  D.  R.  P.  206057;  U.  S.  Pat.  888321  and  907016  (1908). 
EhrHch,  Ber.  42,  36  (1909). 

20.  Eng.  Pat.  3087,  and  9234  (1915). 

21.  Morgan,  Organic  Arsenic  Compounds,  p.  256. 

22.  Danysz,  Compt.  Rend.  (1914)  159,  452. 


CHAPTER  IV 

THE  CHEMOTHERAPY  OF  ARSENIC  COMPOUNDS 

The  selective  action  of  a  compound  for  certain  cells  depends  on 
the  coming  together  of  a  particular  group  in  the  molecule  into 
some  sort  of  chemical  connection  with  the  cell  substance.  In 
1898,  Ehrlich  (Deut.  med.  Woch.,  page  1052)  advocated  the  theory 
that  the  selective  action  of  a  compound  for  certain  cells  must  be 
based  upon  the  penetrability  of  the  drug.  This  difference  of 
affinity  determined  whether  the  drug  had  greater  power  to  de- 
stroy the  parasite  or  to  combine  with  the  protoplasm  of  the  host. 
In  the  one  case  it  is  known  as  a  parasitropic  and  in  the  other 
an  organotropic  substance.  After  many  years  of  investigation 
of  arsenic  compounds,  the  field  of  arsenic  therapy  was  divided 
into  two  sections.  One  was  devoted  to  the  study  of  arsenic  in 
the  pentavalent  form,  the  other,  to  arsenic  in  the  trivalent  form. 

There  are  at  least  three  weU-defined  qualifications  that  a  prep- 
aration must  possess  and  they  are  summed  up  as  follows: — 

1.  The  compound  must  be  non-irritant  and  capable  of  re- 
maining in  perfect  solution  at  the  temperature  and  the  alkalinity 
of  the  tissues. 

2.  It  must  act  quickly  on  the  parasites  before  they  can  acquire 
a  tolerance  to  the  drug. 

3.  When  the  parasites  have  been  expelled  from  the  blood  by 
therapeutic  doses,  there  must  be  no  recurrence  in  a  majority  of 
cases  within  some  fixed  time,  which  will  depend  to  some  extent 
on  the  particular  host  and  the  strain  of  parasites. 

Pentavalent  Arsenic  Compounds 

Along  these  lines  of  research  much  work  has  been  carried  out 
and  certain  arsenic  compounds  have  been  selected  as  partially 
fulfilling  these  requirements.  In  chemical  language  we  have  two 
groups  of  arsenic  compounds,  inorganic  and  organic.     For  use 


26 


THE  TREATMENT  OF  SYPHn.IS 


in  the  present  instance,  only  the  organic  compounds  will  be 
considered.  We  will  deal  first  with  the  pentavalent  arsenic 
preparations  and  then  discuss  the  trivalent  arsenic  compounds. 
Arsenic  has  had  some  reputation  in  the  treatment  of  protozoal 
diseases  since  the  time  of  Fallopius.  The  compounds  containing 
arsenic  in  the  pentavalent  condition  are: — 


/OH 

/CHs 

OH 

OH 

0  =  As— OH 

0  =  As— CH3          0  =  As  ONa 

As  =  0 

\0H 

\ONa                /\| 

/\     ONa 

Arsenic  acid 

Sodium  cacodylate 

V 

\X 

NH2 

NHCOCH3 

Sodium  arsanilate  Sodium  acetyl  arsanilate 
(atoxyl,  soamin)  (arsacetui) 


Biological  examination  shows  that  all  of  these  products  are 
comparatively  nontoxic  when  introduced  into  the  animal  system 
until  changes  take  place  that  liberate  arsenic.  The  arsenic  in 
these  compounds  is  liberated  very  slowly  in  the  system,  thus  pro- 
ducing the  ordinary  therapeutic  effects  of  the  element.  The 
chief  objection  to  this  class  of  compounds  is  found  in  the  fact 
that  they  are  excreted  readily  and  generally  in  an  unchanged 
form.  This  means  that  relatively  large  doses  must  be  adminis- 
tered to  gain  beneficial  results,  while  on  the  other  hand  the  kid- 
neys and  liver  are  suffering  from  a  tremendous  oversupply  of 
arsenic.  Another  objection  is  found  in  the  fact  that  treatment 
with  this  class  of  compounds  is  followed  by  degeneration  of  the 
optic  nerve  and  optic  atrophy.  These  as  well  as  the  therapeutic 
action  are  mainly  due  to  the  reduction  products  which  are  formed 
in  the  organism. 

Pentavalent  arsenic  probably  produces  cumulative  effects 
after  repeated  doses.  Atoxyl  was  found  to  be  very  efficient  in 
tr3rpanosomiasis  but  also  it  was  found  that  in  vitro  there  was 
little  activity  for  the  reason  that  there  was  no  reduction  of  the 
arsenic  to  the  trivalent  condition.  Rohl,  and  Friedberger  {Zeit- 
schrif.  Imunitdts  forschung  u.  exp.  Ther.,  Vol,  I,  1909)  Berl.  klin, 
Woch.  1909,  No.  II,  Berl.  klin,  Woch.,  1908,  No.  j8,  Therap.  Mon- 


CHEMOTHERAPY  OF  ARSENIC  COMPOUNDS  27 

ats,  May,  191 1)  state  that  the  curative  action  probably  depends 
on  the  transformation  of  the  organic  pentavalent  arsenic  com- 
pounds into  trivalent  preparations  which  are  directly  toxic  to 
protozoa  in  the  same  maimer  that  arsenic  pentoxid  is  partly 
reduced  in  the  organism  to  arsenious  acid.  (Binz  and  Schulz, 
Archiv.f.  exp.  Path  u.  Fharm.,  Vol.  II,  page  200,  1879.) 

Furthermore,  pentavalent  compounds  cause  disturbances  of 
the  digestive  system  and  nephritis  as  well  as  toxic  effects  on  the 
general  nervous  system.  When  these  compounds  are  admin- 
istered continuously  characteristic  symptoms  of  arsenic  poison- 
ing are  manifested.  The  pentavalent  organic  arsenic  compounds 
do  not  produce  any  effect  on  trypanosomes  in  vitro  whereas 
trivalent  compounds,  either  organic  or  inorganic,  show  consider- 
able activity.  This  difference  of  therapeutic  action  is  probably 
due  to  the  variability  of  chemical  activity. 

It  seems  to  be  a  well  established  fact  that  all  arsenical  combi- 
nations, which  are  capable  of  reacting  chemically,  are  phar- 
macologically active,  producing  effects  which  in  the  last  analysis 
are  due  to  the  action  of  the  anions,  AsOg  or  ASO4.  The  action 
further  might  be  explained  in  terms  of  energy  changes  in  which 
the  valency  of  the  element  changes  from  pentavalent  to  triva- 
lent. A  similar  theory  is  foimd  in  the  case  of  dyes  in  which  there 
is  a  certain  chromophore  group  in  addition  to  an  anchoring 
group  or  salt-forming  group.  This  group  is  one  in  which  nitro- 
gen is  involved  and  is  well  illustrated  by  the  azo  group — N  =  N — . 

Why  Pentavalent  Compounds  are  Unsatisfactory 

In  conclusion  the  pentavalent  arsenic  compounds  are  unsatis- 
factory, due  to  the  rapid  excretion  of  the  product  and  to  the  fact 
that  the  anatomic  changes  show  degeneration  of  the  optic  nerve 
and  retinal  ganglia  as  well  as  the  cerebral  cell  injury.  Further- 
more the  curative  dose  is  so  close  to  the  toxic  dose  that  it  ren- 
ders most  of  these  products  dangerous,  i.  e.,  the  ratio  of  the  cura- 
tive dose  to  the  tolerated  dose  is  a  small  fraction.  With  a  large 
dose  for  curative  purposes  it  means  an  increased  effort  on  the 
part  of  the  kidneys  and  liver  to  withstand  this  attack.  It  should 
not  be  inferred  that  this  class  of  compounds  do  not  have  any 


28 


THE  TREATMENT  OF  SYPHILIS 


therapeutic  action  but  it  is  a  fact  that  in  most  cases  they  are  less 
satisfactory  than  the  compounds  containing  trivalent  arsenic. 


Trivalent  Arsenic  Compounds 

The  trivalent  compounds  of  arsenic  are  many  in  number  but 
only  a  few  has  been  of  practical  use  inasmuch  as  the  adaptabihty 
of  many  of  them  has  not  been  entirely  satisfactory.  From  this 
large  number  a  few  have  been  selected  because  the  ratio  between 
the  etiotropic  efficiency  and  the  toxicity  has  been  more  favor- 
able. In  the  case  of  salvarsan  this  ratio,  according  to  the  Hata 
method,  was  i :  58.  Two  products  of  this  type  have  been  used 
very  extensively  during  the  past  ten  years.  However,  this  is  no 
indication  that  other  useful  products  cannot  be  obtained.  A  few 
structural  formulas  will  indicate  the  organic  preparations  that 
illustrate  trivalent  arsenic  in  combination  with  ring  compounds. 


OH 

OH 

OH 

As  =  0 

As  =  0 

As  =  0 

/\ 

OH 

/\ 

OH 

/^ 

OH 

\y 

\y 

NO2 

\y 

NO2 

NH2 

HH2 

OH 

Arsanilic  acid. 

Nitro  arsanilic 

Nitro-oxy  phenyl 

pentavalent 

acid,  pentavalent 

arsinic  acid, 
pentavalent 

As  =  0 

As 

=     As 

/\ 

/\ 

/\ 

\y 

NH2 

\/ 

NH2 

\X 

NH2 

OH 

01 

I           OH 

Amino  oxy  phenyl  arsenoxide. 

Sa 

ivarsan  base 

Twice  as  curative 

as  salvarsan 

Tr 

ivalent  arsenic 

6  times  as  toxic. 

Triv 

rale 

nt  arsenic 

As 


=         As 


As     = 


As 


\J  NH2HCI  'vJ  NH2HCI     \J  NH2  \y  NH2 
OH  OH  ONa         ONa 

Salvarsan  sodium 


As     = 


As 


OH  OH 

Salvarsan 


S/  NH2  \/NHCHOHOSNa 
ONa         ONa  OH  OH 

Neosalvarsan 


CHEMOTHERAPY  OF   ARSENIC   COMPOUNDS 


29 


Trivalent  Arsenic  more  Potent  Therapeutically 

In  the  case  of  trivalent  arsenic  the  effective  dose  can  be  in- 
troduced with  much  greater  safety  and,  according  to  EhrHch, 
the  more  powerful  therapeutic  action  is  due  to  the  radical  con- 
taining the  trivalent  arsenic,  the  importance  of  which  was  ren- 
dered apparent  in  experiments  with  trypanosomes  and  also  to 
the  introduction  of  hydroxy  radicals  in  the  para  position  in  the 
molecules,  in  which  the  amido  radicals  are  in  the  ortho  position, 
relatively  to  the  hydroxy  radicals.  In  the  case  of  these  double 
ring  compounds,  there  is  a  double  arsenic  action  due  to  the  scis- 
sion of  the  salvarsan  (or  neosalvarsan)  molecule  betvv^een  the  two 
arsenic  groups  giving  the  action  of  two  trivalent  arsenic  mole- 
cules. The  chemical  change  which  takes  place  in  the  blood  is 
probably  represented  by  the  following  formulas:  (Ernest  Sie- 
burg — Zeitschr.  physiol.  chem.,  Vol.  97,  p.  53,  1916.) 


As     = 


As 


ONa 


NH2  V 


NH2 


Protein  combination 


ONa 


OH 

As  =  0 

As  =  0 

/\ 

/\ 

OH 

\y 

NH2 

\y 

NH2 

OP 

[ 

OH 

Amino  oxy  phenyl     2  amino  3  oxy 
arsenoxide  phenyl  arsenic 


acid 


\ 


3  oxyl  phenyl  arsinic  acid 


NH2 
/\ 
or 

NH2       V 

OH  OH 

amino  phenols 


CHAPTER  V 

INDICATIONS,      CONTRAINDICATIONS     AND      EFFICIENCY      OF     AR- 

SPHENAMINE 

Particular  Indications  for  Arsphenamine  Treatment 

It  should  not  be  accepted  as  a  fixed  rule  that  all  cases  of  lues 
are  to  receive  arsphenamine  treatment.  As  elsewhere  discussed, 
there  are  certain  definite  contraindications  to  the  use  of  the 
arsenical  preparations.  It  is  generally  accepted,  however,  that 
particular  indications  for  the  use  of  arsphenamine  can  be  laid 
down  and  it  is,  therefore,  advised  that  the  product  be  utilized  in: 

1.  AU  cases  of  early  syphilis  possessing  distinctive  symptoms. 

2.  In  primary  cases  as  an  abortive  agent. 

3.  In  tertiary  and  latent  cases  with  a  positive  Wassermaim. 

4.  In  tabes  and  paresis,  congenital  syphilis,  maUgnant  syphilis, 
painful  periostitis  and  gummata. 

5.  In  cases  in  vv/^hich  mercury  cannot  be  used  to  advantage, 
when  the  patients  become  easily  salivated  or  in  which,  after  long 
continued  mercurial  treatment,  the  Wassermaim  reaction  re- 
mains positive. 

Contraindications  to  Arsenical  Therapy 

Arsphenamine  and  neoarsphenamine  cannot  be  used  indis- 
criminately upon  every  luetic  person.  Therefore  a  careful 
physical  examination  of  the  patient  is  an  important  essential. 
If  any  of  the  following  conditions  exist  these  remedial  agents 
should  be  withheld  untU  the  offending  obstacle  has  been  re- 
moved if  such  is  possible: 

Recent  cases  of  myocarditis  and  valvular  disease. 

Nephritis,  not  of  syphilitic  origin. 

Marked  diabetes. 

Advanced  tuberculosis. 


INDICATIONS,  ETC.,   OF  ARSPHENAMINE  31 

Any  diseases  of  the  organs  of  the  thoracic  and  abdominal 
cavities. 

Persons  of  very  advanced  years. 

Persons  possessing  an  idiosyncrasy  against  arsenic. 

Following  acute  diseases,  especially  when  depressing  sequelae 
are  present. 

Dr.  H.  H.  Morton  of  Brooklyn  suggests  that  salvarsan  be 
used  with  extreme  caution  in  brain  syphilis,  but  directs  attention 
to  the  fact  that  in  acute  optic  neuritis,  choroiditis  and  inter- 
stitial keratitis,  it  clears  up  the  lesions  with  great  rapidity. 

The  urine  of  each  patient  should  be  examined  before  the 
administration  of  the  drug  and  cases  showing  a  renal  involve- 
ment should  be  denied  arsphenamine  or  it  should  be  given  in  very 
small  doses. 

After  each  injection  of  salvarsan  and  neosalvarsan  the  urine 
should  also  be  examined,  so  that  the  physician,  at  all  times,  may 
be  familiar  with  the  condition  of  the  kidneys. 

A  trace  of  albumin  and  a  few  casts  may  be  found  in  the  urine 
the  morning  after  an  injection  of  salvarsan.  This  should  not  be 
considered  a  contraindication  unless  considerable  albumin  is 
present  and  the  number  of  casts  on  the  slide  are  in  excess  of  ten. 

The  Therapeutic  Effects  of  Arsphenamine 

One  injection  of  arsphenamine  aids  materially  in  rendering 
the  patient  non-infectious  to  those  about  him. 

The  spirocheta  palKda  disappears  from  the  chancre  in  from 
twelve  to  forty-eight  hours  after  salvarsan  injection  and  the 
lesion  usually  heals  in  from  seven  to  ten  days. 

Condylomata  and  mucous  patches  disappear  within  a  few 
days  after  the  injection,  as  do  skin  and  bone  gummata. 

Dr.  H.  H.  Morton  says  the  "effects  of  salvarsan  in  malignant 
syphilis  are  brilliant,  especially  in  the  cases  which  are  refractory 
to  mercury  and  iodides." 

Mortality  in  congenital  S3rphiiis  has  been  considerably  lessened 
since  arsphenamine  treatment  was  instituted. 

Salvarsan  reUeves  the  "lightning  pains"  of  tabes,  although 


32  THE  TREATMENT  OF  SYPHILIS 

it  cannot  restore  the  nerve  tissue  which  has  been  destroyed. 
Tabetic  and  paretic  patients  are  generally  much  improved  by  the 
use  of  salvarsan  and  in  some  cases  the  progress  of  the  disease  is 
arrested. 

The  intraspinous  use  of  arsphenamine  in  these  cases  is  advo- 
cated by  some  and  decried  by  others,  but  adherents  of  both  intra- 
spinous and  intravenous  methods  seem  to  be  of  the  opinion  that 
improvement  usually  follows  the  employment  of  arsphenamine. 

Arsphenamine's  Therapeutic  Efficiency 

The  efficiency  of  arsphenamine  as  a  curative  agent  in  the 
treatment  of  lues  has  been  so  definitely  established  during  the 
years  of  its  employment  that  this  subject  needs  only  a  passing 
word. 

The  testimony  of  a  few  authorities  will  demonstrate  to  the 
casual  reader  the  place  the  drug  has  made  for  itself  in  the  world 
of  therapy. 

Col.  E.  B.  Vedder,  U.  S.  Army  {Syphilis  and  the  Public  Health j 
p.  259,  1918),  says  ''it  has  been  sufficiently  demonstrated  that 
salvarsan  is  a  specific  in  the  treatment  of  syphilis,  and  while  the 
fallacy  of  our  original  hopes  of  a  '  therapia  sterilizans  magna '  is 
now  apparent,  this  drug  still  remains  the  most  potent  remedy 
which  we  can  command.  Although  it  is  still  possible  to  treat 
syphilis  by  mercury  alone  or  in  combination  with  the  iodides 
in  the  later  stages  of  the  disease,  such  treatment  is  distinctly 
inferior  in  its  results  to  the  proper  combination  of  salvarsan  and 
mercury." 

Dr.  Loyd  Thompson  of  Hot  Springs  {Syphilis^  p.  232,  1918) 
says  "chancres,  the  syphilodermata,  and  the  syphilomycoder- 
mata  heal  with  startling  rapidity,  the  treponemata  sometimes 
disappearing  from  the  lesions  within  twelve  to  twenty-four 
hours,  while  the  symptoms  of  visceral  syphilis  and  syphilis  of 
the  nervous  system  usually  diminish  and  may  disappear  alto- 
gether following  its  (salvarsan's)  use." 

Dr.  Cole  states  in  the  Ohio  State  Medical  Journal  that  "sal- 
varsan is  the  most  powerful  drug  now^  at  the  physician's  com- 


INDICATIONS,  ETC.,   OF  ARSPHENAMINE  33 

mand  in  the  treatment  of  syphilis  and  when  wisely  administered 
is  practically  free  from  all  danger  or  marked  unpleasantness." 
He  adds  that  herein  lies  the  great  value  of  salvarsan  (after  an 
injection  of  salvarsan)  that  in  twenty-four  to  forty-eight  or 
seventy-two  hours  the  acute,  contagious  lesions  on  any  patient 
will  be  so  changed  that  he  will  be  no  longer  a  direct  menace  to 
his  friends  and  society.  Cole  believes  that  practically  every  case 
of  cerebro-spinal  syphilis  with  a  high  cell  count  in  the  spinal 
fluid  will  react  well  and  quickly  to  salvarsan.  He  has  seen 
"lightning  pains"  disappear  after  one  or  two  injections — though 
this  is  not  always  true. 

Nine  Indications  for  Salvarsan 

Dr.  G.  F.  Lydston  of  Chicago  states  in  the  Medical  Standard 
that  he  is  convinced  from  careful  observation  that  salvarsan  is 
of  great  value  in  meeting  the  following  indications : 

First.  Prompt  removal  of  genital  lesions  thus  lessening: 
first,  the  danger  of  infecting  others;  second,  the  danger  of  detec- 
tion; third,  local  discomfort;  fourth,  the  danger  of  serious  com- 
plications. 

Second.  The  prevention  or  prompt  removal  of  disfiguring  skin 
lesions. 

Third.  Precocious  or  malignant  syphilis. 

Fourth.  Cases  resistant  to  mercury. 

Fifth.  Early  nerve,  brain  and  visceral  lesions,  with  the  excep- 
tion of  renal  syphilis  in  which  salvarsan  is  especially  dangerous. 

Sixth.  Cases  of  syphilitic  cachexia  or  anemia,  which  often 
consist  of  a  combiaation  of  overtreatment  and  syphilis. 

Seventh.  Syphilis  involving  the  organs  of  special  sense,  ex- 
cepting marked  lesions  involving  the  retina.  The  wisdom  of 
employing  salvarsan  here  is  still  subjudice. 

Eighth.  Early  tabes  and,  in  some  late  cases,  to  relieve  severe 
pain  or  involvement  of  the  sphincters. 

Ninth.  Infantile  syphilis. 

In  aU  cases  mercury  should  be  regarded  as  still  our  sheet 
anchor  in  syphilis. 


34  THE  TREATMENT  OF  SYPHILIS 

Arsphenamine  as  a  Prophylactic 

It  is  a  matter  of  common  belief  that  arsphenamine  introduced 
into  the  system  as  soon  as  the  initial  lesion  has  manifested  itself, 
or  before,  in  the  event  the  recipient  feels  he  has  been  inoculated 
with  the  spirocheta  palUda,  will  act  as  a  prophylactic. 

Indeed  the  abiUty  of  arsphenamine  to  prevent  syphihs  from 
obtaining  a  foothold  in  the  system  has  been  exemplified  in  a 
great  number  of  cases.  One  of  the  latest  is  the  report  by  Dr.  A.  C. 
Magian  (Bull,  de  I' Acad,  de  Med.,  Paris,  May  20,  19 19)  to  the 
effect  that  on  March  21,  1918,  in  the  French  Hospital  at  Man- 
chester he  inoculated  himself  in  the  presence  of  twenty  physicians 
with  some  of  the  serous  fluid  from  a  chancre.  Less  than  an 
hour  afterward  he  was  given  an  injection  of  arsphenamine,  0.6 
gram.  None  of  the  classical  symptoms,  either  local  or  general, 
which  would  indicate  syphilis,  appeared,  and  although  he  had 
a  Wassermann  taken  monthly  for  a  year  since  that  time  it  has 
been  constantly  negative  and  he  has  shown  no  indication  what- 
ever of  having  the  spirocheta  pallida  in  his  system. 

We  have  known  cases  in  which  the  physician  inadvertently 
pierced  his  skin  with  a  needle  which  had  been  utilized  for  the  in- 
jection of  salvarsan.  As  a  matter  of  precaution,  the  physician 
immediately  had  himself  injected  with  salvarsan  and  no  signs 
of  lues  ever  developed. 

We  are  of  the  opinion  that  salvarsan  used  in  this  way  will  pre- 
vent syphilis. 

Arsphenamine  as  a  Medicinal  Agent  in  Other  than  Luetic 
Conditions 

Arsphenamine  seems  to  be  of  value  in  conditions  other  than 
lues.  In  the  tropics  it  is  used  as  a  more  or  less  routine  treatment 
in  filaria,  frambesia,  malaria,  recurrent  fever,  tick  fever  and  marsh 
fever,  and  it  has  been  recommended  by  some  physicians  in  those 
conditions  in  which  arsenic  is  indicated,  such  as  psoriasis,  leuko- 
derma, pemphigus,  and  the  like. 

Vincent's  angina,  pyorrhea  and  "  trench  mouth "  are  also 
among  the  conditions  in  which  arsphenamine  has  been  employed. 


INDICATIONS,  ETC.,  OF  ARSPHENAMINE  35 

No  particular  recommendation  is  made  regarding  the  employ- 
ment of  salvarsan  in  these  diseases,  as  we  have  had  no  experience. 
We  are  of  the  opinion,  however,  that  the  use  of  arsphenamine 
will  be  much  more  general  in  the  future  as  research  evolves  ways 
and  means  for  its  use. 

The  great  war  has  brought  about  an  entire  change  in  treating 
many  conditions.  One  of  the  most  unique  has  been  described 
by  Dr.  A.  Brechot,  of  the  French  Army  {Paris  Medicate,  May  24, 
1919).  He  employed  neoarsphenamine  intravenously  for  the 
purpose  of  preventing  or  curing  septicemia,  and  as  an  adjuvant 
in  furthering  and  hastening  the  healing  of  wounds.  He  found 
that  in  such  conditions  an  intravenous  injection  of  neoar- 
sphenamine, 0.3  gram,  was  followed  by  great  improvement. 
According  to  the  cases  which  he  describes,  the  action  of  neoar- 
sphenamine became  noticeable  at  least  by  the  third  day,  and  its 
effect  was  most  beneficial  in  acute  septicemias  which  were  not 
complicated  with  marked  local  lesions. 

It  was  also  of  benefit  in  infected  wounds  in  the  soft  parts  which 
were  of  recent  origin  and  which  had  become  gangrenous.  He  did 
not  obtain  beneficial  results  when  neoarsphenamine  was  em- 
ployed in  conditions  showing  advanced  suppuration  or  where 
there  was  an  enormous  amount  of  gangrene. 

The  Comparative  Use  of  Arsphenamine  and  Neoarsphenamine 

Each  of  these  products  has  its  ardent  admirers  among  physi- 
cians. Some  men  insist  that  one,  and  others  the  other  is  the 
drug  of  choice.  Personally,  we  believe  that  a  great  many  things 
enter  into  the  matter  of  a  choice  between  salvarsan  and  neo- 
salvarsan.  Some  patients  failing  to  improve  with  one,  make 
marked  improvement  under  the  other,  and,  believing  as  we  do 
that  every  case  of  syphilis  must  be  individualized  and  treated 
according  to  the  particular  needs  of  the  affected  person,  it  is 
impossible  to  make  an  unqualified  statement  as  to  the  value  of 
one  as  compared  with  the  other. 

Drs.  Wm.  B.  Trimble  and  John  J.  Rothwell  of  New  York 
(/.  A.  M.  A.,  page  1984,  1916)  made  an  interesting  study  based 


36  THE  TREATMENT  OF  SYPPIILIS 

on  the  treatment  of  no  patients,  and  reached  the  conclusion 
that  neosalvarsan  is  superior  to  saivarsan,  being  much  easier 
of  administration,  less  likely  to  cause  severe  reaction,  and  pro- 
ducing a  greater  percentage  of  negative  results. 

Dr.  OUver  S.  Ormsby  of  Chicago  (/.  A.  M.  A.,  page  949, 1917), 
says  that  saivarsan  and  neosalvarsan  are  the  most  eflfi.cient  drugs 
yet  discovered  in  the  treatment  of  syphilis.  As  to  a  choice  be- 
tween the  two,  Ormsby  believes  the  extensive  use  of  both  pro- 
claims their  efficiency,  so  that  individual  circumstances  with  the 
physician  and  patient  must  decide  which  is  to  be  selected.  He 
says  the  apparent  preponderance  of  opinion  that  saivarsan  is 
more  eflScient  is  offset  to  a  degree  by  the  difficulties  of  its  admin- 
istration and  the  more  frequent  reactions  following  its  use. 

Research  work  and  comparative  tests  will  in  the  not  distant 
future  do  much  toward  demonstrating  the  comparative  value 
of  the  two  drugs. 

It  is  admitted  that  from  the  standpoint  of  the  general  practi- 
tioner neoarsphenamine  is  the  product  of  choice. 


CHAPTER  VI 

A  PLAN  FOR  ANTILUETIC  TREATMENT 

Eternal  vigilance  is  the  price  of  freedom  from  the  spirocheta 
pallida.  Immediate,  consistent,  persistent  and  proper  treatment 
is  necessary  to  overcome  the  ravages  of  sj^hiHs.  As  soon  as  a 
diagnosis  of  lues  is  made,  it  is  the  duty  of  the  physician  to  in- 
stitute treatment.  We  believe  that  the  great  majority  of  sores 
on  the  penis  are  likely  to  be  chancres  and  we  make  it  a  rule  to  so 
regard  aU  sores  that  put  in  an  appearance  ten  days  or  longer 
after  exposure.  It  is  far  better  to  treat  a  chancroidal  case  as 
if  it  were  specific  than  to  "sHp  up"  on  a  case  of  chancre.  It  is 
well  to  bear  in  mind  that  many  sores  diagnosed  as  chancroids  re- 
veal both  Ducrey's  bacillus  and  the  spirocheta  paUida  and  con- 
sequently demand  antiluetic  treatment. 

Dark  field  illmnination  should  be  used  on  all  penile  sores  as 
soon  as  seen,  and  little  difficulty  is  experienced  in  demonstrating 
the  presence  of  the  spirochete  if  it  is  in  the  field.  This  is  proof 
positive  of  the  disease. 

In  certain  instances  it  is  possible  to  abort  syphilis  by  the  most 
vigorous  treatment. 

Some  authorities  advise  the  excision  of  the  chancre  as  soon  as 
it  appears  in  the  belief  that,  if  taken  in  time,  the  spirochetes  will 
not  be  able  to  penetrate  the  surrounding  tissue,  and  we  beheve 
it  is  better  to  be  rid  of  the  lesion  if  it  is  so  situated  that  its  re- 
moval will  cause  no  deformity. 

Prompt  Treatment  Demanded 

As  soon  as  the  diagnosis  has  been  made,  it  is  our  custom  to  give 
an  intravenous  injection  of  0.3  gram  salvarsan  or  0.45  gram 
neosalvarsan,  or  in  the  case  of  a  woman  0.2  gram  salvarsan  or 
0.3  neosalvarsan.  If  well  borne  by  the  patient,  0.4  gram  sal- 
varsan or  0.6  gram  neosalvarsan  is  given  five  days  later. 


38  THE  TREATMENT  OF  SYPHILIS 

Mercury,  preferably  one-fourth  to  one-half  grain  of  the  bi- 
chlorid  in  the  form  of  a  coUapsule,  is  given  hypodermically  in 
the  buttock  two  days  after  the  first  injection  of  salvarsan  or 
neosalvarsan  and  this  is  repeated  three  times  a  week  for  twelve 
weeks.  If  an  insoluble  mercury  is  desired  we  use  the  salicylate 
in  collapsules  of  one  grain  weekly. 

Salvarsan  or  neosalvarsan  is  then  administered  at  seven-day 
intervals  until  six  more  doses  have  been  used,  making  the  course 
number  eight. 

When  taken  early,  these  cases  show  a  negative  Wassermann 
and  it  is  our  object  to  keep  the  reaction  negative.  One  month 
after  the  last  intramuscular  injection  of  mercury  a  Wassermann 
is  taken.  If  negative,  another  is  taken  one  month  later,  and,  if 
the  result  is  the  same,  we  wait  two  months  before  having  another 
examination  made.  If  still  negative  we  have  Wassermanns  done 
bimonthly  for  two  years,  by  which  time,  if  the  reaction  continues 
negative,  we  feel  that  a  cure  has  been  effected. 

If,  on  the  other  hand,  the  first  reaction  shows  positive,  we 
repeat  the  course  of  salvarsan  and  mercury  treatment  and 
follow  this  up  until  a  permanent  negative  is  obtained. 

It  is  not  always  possible  to  see  our  patients  at  the  time  the  in- 
itial lesion  presents  itself.  Many  of  the  cases  of  lues  which  appear 
in  the  physician's  office  are  beyond  the  primary  stage  and  abor- 
tion of  the  disease  is  out  of  the  question. 

The  Treatment  of  Longer  Standing  Cases 

It  is  necessary,  in  these,  to  institute  intensive  treatment,  for 
it  is  on  this  rock  that  we  must  erect  our  therapeutic  structure. 
Many  a  case  has  gone  down  before  the  gales  of  disease  because 
the  house  of  therapy  was  built  upon  the  sands  of  infrequent  and 
inconsistent  treatment. 

As  with  the  attempt  to  abort  syphilis,  we  start  the  patient 
out  with  0.3  gram  salvarsan  or  0.45  gram  neosalvarsan  (if  a 
woman,  the  dose  is  respectively  0.2  gram  salvarsan  or  0.3  gram 
neosalvarsan).  Two  days  later  we  inject  hypodermically  in  the 
buttock  a  collapsule  of  ^  or  3^  grain  mercuric  bichlorid.    Three 


A  PLAN  FOR  ANTILUETIC  TREATMENT  39 

days  later  comes  0.4  gram  salvarsan  or  0.6  gram  neosalvarsan. 
If  all  is  well,  salvarsan  or  neosalvarsan  is  continued  at  weekly 
intervals  until  eight  injections  have  been  given  and  mercury  is 
given  three  times  weekly  at  intervals  for  twelve  weeks,  unless  the 
insoluble  form  is  employed,  in  which  case  the  injections  are  ad- 
ministered weekly.  The  kidneys  must  be  watched  for  possible 
irritation.  The  action  of  the  salvarsan  kills  most  of  the  spiro- 
chetae  palHdae,  while  the  mercury  destroys  the  spirillae  which  are 
to  be  found  in  organs  beyond  the  reach  of  the  arsenic. 

Four  weeks  after  the  last  injection  of  mercury,  a  Wasser- 
mann  is  taken.  If  positive,  the  salvarsan-mercury  course  is  re- 
peated and  is  so  continued  until  a  negative  is  obtained. 

If  negative,  the  same  routine  obtains  as  in  the  abortive  plan. 

When  a  case  is  taken  early,  one  course  of  treatment  is  likely 
to  result  in  a  negative  reaction,  and  the  earlier  we  start  intensive 
treatment  the  more  likely  are  we  to  get  negatives. 

Iodides  Demanded  in  Tertiary  and  Latent  Cases 

In  tertiary  and  latent  cases  several  courses  of  treatment  may 
be  necessary  to  reach  the  goal.  Potassium  iodid  must  not  be 
forgotten  in  these  cases,  particularly  if  gummata  or  periosteal 
lesions  or  other  manifestations  of  late  syphilis  are  present.  If 
the  disease  has  affected  the  nervous  system  it  is  especially  in- 
dicated. To  be  effective  potassium  iodid  must  be  pushed  in 
heavy  doses.  The  drug  should  also  be  used  in  tertiary  syphilis 
with  a  persistently  positive  reaction,  without  involvement  of  the 
central  nervous  system.  Indeed  there  are  cases,  which,  though 
apparently  clinically  cured,  are  serologically  not  cured,  that  is, 
they  seem  to  be  permanently  positive.  Such  cases  are  termed 
''Wassermann  fast"  and  in  the  Hght  of  our  present  knowledge 
it  seems  impossible  to  change  these  positive  cases  to  negative. 

If  a  patient  shows  a  negative  and  later  develops  a  positive, 
we  have  proof  that  he  still  has  a  focus  of  infection  in  his  body  and 
must  be  given  another  course  of  treatment. 

The  provocative  injection  plays  its  part  as  related  in  the  chap- 
ter entitled  "Provocative  Wassermann  Reaction." 


40  THE  TREATMENT  OF  SYPHILIS 

We  believe  good  treatment  calls  for  the  use  of  this  procedure 
in  early  cases.  If  negative  reactions  result,  we  feel  that  we  have 
reason  to  pronounce  a  cure.  If  spirochetae  are  still  in  the  system, 
we  should  know  it,  and  the  provocative  injection  is  the  only 
agent,  except  time,  which  wiU  make  their  presence  known. 

In  tertiary  and  latent  cases  a  Wassermann  of  the  spinal  fluid 
must  be  made  and  the  reaction  of  both  blood  and  spinal  fluid 
must  be  repeatedly  negative  before  the  case  can  be  pronounced 
cured. 

Salvarsan  and  Mercury  Necessary 

Dr.  C.  L.  Barewald  of  Davenport,  Iowa,  in  a  paper  read  before 
the  Scott  County  Medical  Society,  March  4,  1919,  states  that 
after  using  the  various  preparations  on  the  market  he  found  that 
salvarsan  is  by  far  the  best,  as  it  gives  better  results  and  more 
efficient  elimination.  He  has  given  more  than  two  thousand 
intravenous  injections  of  salvarsan  without  experiencing  any 
bad  results.  He  emphasizes  the  fact  that  syphilis  is  not  cured 
by  salvarsan  alone  and  that  mercury  must  be  included  in  the 
treatment.  He  gives  salvarsan  once  a  week  for  eight  weeks  and 
at  the  same  time  uses  mercury,  preferably  by  inunction. 

Intensive  Salvarsan  Treatment 

Dr.  S.  Politzer,  of  New  York  {Jour.  Cut.  Dis.,  Sept.,  1916)  is 
an  advocate  of  the  most  intensive  type  of  salvarsan  treatment  in 
acute  cases.  As  soon  as  a  positive  diagnosis  is  made,  he  gives 
three  injections  of  salvarsan  in  large  doses  at  intervals  of  twenty- 
four  hours,  and  follows  this  by  a  course  of  eight  weekly  injections 
of  salicylate  of  mercury.  If  the  treatment  is  begun  after  the 
appearance  of  the  rash,  this  course  of  salvarsan  and  mercury- 
treatment  is  repeated  after  a  pause  of  two  months  and  again 
after  a  similar  interval.  After  three  courses  within  the  first  year, 
he  suspends  treatment  if  the  Wassermann  reaction  is  negative. 

If  the  treatment  is  begun  a  year  or  more  after  infection,  treat- 
ment should  be  continued  imtU  negative,  and  two  more  addi- 
tional courses  of  treatment  given,  even  though  the  reaction 
may  be  negative. 


A  PLAN  FOR  ANTILUETIC  TREATMENT  41 

Dr.  J.  L.  Murray  of  Toledo  {Ohio  State  Med.  Jour.)  is  an 
advocate  of  a  similar  method.  His  plan  is  to  give  a  small  dose 
of  salvarsan  on  three  successive  days,  followed  by  eight  weekly 
injections  of  salicylate  of  mercury. 

In  the  secondary  stage,  Murray  gives  these  intensive  courses 
at  intervals  of  three  or  four  months  regardless  of  the  Wassermann 
reactioii. 


CHAPTER  Vn 

THE  TECHNIC  OF  ARSPHENAMTNE  ADMINISTRA.TION 

The  Intravenous  Administration  of  Arsphenamine 

The  fundamental  principle  of  drug  administration  is  based 
upon  the  proper  usage  of  the  remedial  agents  which  are  to  be 
employed.  Carelessness  in  technic  or  lack  of  necessary  informa- 
tion regarding  a  drug  has  often  seriously  injured  good  prepara- 
tions. 

Three  prime  requisites  stand  out  as  necessary  to  the  satisfac- 
tory administration  of  a  drug:  (i)  knowledge  of  the  drug  and  its 
properties;  (2)  a  perfect  understanding  of  the  patient  and  his 
idiosyncrasies;  (3)  confidence  and  due  precaution  on  the  part 
of  the  administrator. 

In  the  injection  of  any  drug  by  the  intravenous  method 
rigid  asepsis  is  a  most  important  factor. 

During  the  past  two  years  over  two  million  doses  of  arsphena- 
mine have  been  administered  with  varying  degrees  of  success. 
After  a  careful  study  of  the  situation  in  hospital  and  private 
practice,  we  have  evolved  a  method  of  administration,  which 
provides  safety  and  precaution  in  the  highest  degree  for  the 
physician  and  the  patient. 

Preparation  of  the  Drug 

The  apparatus  necessary  for  the  administration  of  salvarsan 
includes : 

An  adjustable  bracket  or  stand,  and  a  table  for  this  stand  to 
rest  upon. 

Two  glass  cylinders  of  250  c.  c.  capacity;  one  for  holding  the 
solution  of  salvarsan  and  the  other,  distilled  water. 


Cd 

n 

!z; 

o 

S 
t 

c 
o 

u 

W 

r; 

p^ 

m 

Pi 

e 

< 

o 

o 

;-i 

^ 

cj 

o 

«) 

H 

X 

y 

■ — ) 

1— . 

rt 

'Z 

M 

t) 

-1 

n 

J^ 

W 

.^ 

> 

^ 

f 

r^ 

Pi 

H 

rt 

y, 

m 

1— 1 

r. 

W 

CJ 

m 

*"• 

H 

-(-> 

rrt 

Ut 

rt 

a 

cu 

cj 

OJ 

J3 

H 

TECHNIC  OF  ARSPHENAMINE  ADMINISTRATION       43 

Rubber  tubing  leading  from  each  cylinder  to  a  Morton  three- 
way  stopcock,  on  the  end  of  which  the  needle  is  attached. 

Fordyce  or  other  needles  of  fine,  medium  and  large  calibre, 
the  size  to  be  determined  by  the  vein. 

2  c.  c.  syringe  and  hypodermic  needle  for  epinephrin. 

An  abundant  supply  of  freshly  prepared  double  distilled  and 
sterilized  water,  or  0.4  per  cent  sodium  chlorid  solution. 

A  tourniquet  of  rubber  tubing  or  a  rubber  catheter. 

A  glass  cylinder  (250  c.  c.)  in  which  to  mix  the  solution. 

Sterile  gauze  and  sterile  cotton. 

A  glass  funnel  for  filtering  the  solution. 

Tincture  of  iodin  or  alcohol. 

A  bottle  of  freshly  prepared  C.  P.  sodium  hydroxid — 15  per 
cent  or  normal  sodium  hydroxid — 4  per  cent. 

A  bottle  of  collodion  for  sealing  the  point  of  the  puncture  after 
administration. 

Lastly,  the  drug  itself. 

Apparatus. — The  mixing  cylinder  should  be  thoroughly  washed 
with  distilled  water  and  drained  for  a  few  minutes,  the  stopper 
tied  loosely  to  the  neck  of  the  cylinder  and  then  the  stopper 
and  neck  covered  with  a  piece  of  gauze.  The  combination 
should  be  sterilized  by  dry  heat  and  when  cool,  the  stoppers 
inserted  without  removing  the  gauze.  The  gauze  is  tied  around 
the  upper  part  of  the  stopper  so  that  it  can  be  used  as  a  protection 
to  the  stopper  during  its  subsequent  use  in  mixing. 

There  is  no  objection  to  the  method  of  boiling  the  cylinder  for 
twenty  minutes  in  the  sterilizer  except  that  it  requires  additional 
sterile  distilled  water  for  rinsing  before  use.  All  of  the  other 
apparatus  should  be  sterilized  just  before  using  and  extreme 
care  should  be  exercised  to  avoid  using  the  apparatus  while  it 
is  still  hot.  The  reason  for  this  care  is  to  avoid  the  decomposition 
of  the  salvarsan  solution  before  it  is  used. 

It  is  a  well-known  chemical  fact  that  too  hot  water  is  one  of 
the  chief  factors  in  causing  decomposition  and  subsequent  re- 
actions. Just  before  using  the  apparatus,  it  should  be  rinsed  out 
with  sterile  distilled  water. 


44  THE  TREATMENT  OF  SYPHILIS 

DistiUed  Water 

The  water  problem  in  the  making  of  salvarsan  solutions  is  a 
question  of  real  importance  to  physicians,  especially  to  those 
who  have  occasion  to  administer  arsphenamine  at  infrequent 
intervals.  It  is  at  all  times  necessary  to  employ  freshly  distilled 
water  and  not  that  which  may  be  several  days  or  weeks  old. 
It  is  absolutely  imsafe  to  send  to  a  neighboring  town  for  distilled 
water  or  the  15  per  cent  sodium  hydroxid,  and  by  so  doing  the 
physician  takes  a  considerable  risk. 

It  is  a  well-known  fact  that  water  contains  many  inorganic 
salts  as  well  as  much  nitrogenous  matter.  To  remove  these 
impurities,  the  process  of  distillation  is  used  but,  through  neg- 
lect, some  of  the  water  may  be  allowed  to  boil  over  into  the  side 
tube  and  thereby  vitiate  the  efforts  of  purification.  Water  also 
contains  volatile  material  of  a  gaseous  nature  and  it  is  important 
to  remove  these  impurities.  Time  and  space  do  not  permit  a 
detailed  discussion  of  a  method  which  will  yield  what  is  known  as 
"chemically  pure"  water  or  "conductivity  water."  However,  a 
general  method  is  presented  for  securing  relatively  large  quan- 
tities of  water  suitable  for  intravenous  use. 

Any  suitable  type  of  metal  distilling  apparatus  provided  with  a 
block  tin  condenser  will  answer  the  purpose.  A  manufacturer  of 
chemical  apparatus  can  easily  provide  this  type.  In  using  it, 
care  should  be  used  in  preventing  the  possibility  of  mechanical 
overflow.  This  provides  a  roughly  distiUed  water  contaminated 
with  volatile  gases.  This  grade  of  distilled  water  should  be  used 
for  obtaining  sterile,  freshly  glass-distilled  water.  There  are 
several  ways  of  carrying  out  this  procedure. 

The  simplest  technic  is  to  place  the  water  in  any  glass-distilling 
apparatus  and  add  calcium  oxid  or  alkaline  permanganate  to 
absorb  carbon  dioxid  and  destroy  organic  matter.  The  con- 
tents should  be  heated  to  boiling  and  the  distillate  collected  in  a 
flask  suitable  for  later  sterilization  if  the  water  is  not  to  be  used 
as  soon  as  cool.  A  continuous  distillation  can  be  carried  on  by 
this  method. 


Distilling  Apparatus 

A  simple  type  for  physicians  who  have  no  gas,  elec- 
tricity or  running  water,  or  who  lack  any  one  of 
these  three  conveniences.  Description  of  this  ap- 
paratus is  found  on  page  45. 


TECHNIC  OF  ARSPHENAMINE  ADMINISTRATION        45 

A  Simple  Distilling  Apparatus 

In  case  only  a  relatively  small  quantity  is  to  be  utilized,  omit- 
ting the  permanganate,  it  is  well  to  distill  off  at  least  one  fourth 
and  discard  it  and  to  coUect  the  remainder  for  use.  For  the 
benefit  of  those  who  are  limited  in  their  facilities  the  apparatus 
shown  in  the  accompanying  picture  is  presented. 

This  type  of  apparatus  is  designed  for  those  who  lack  gas, 
electricity  and  running  water  or  any  one  of  the  three  conven- 
iences. It  consists  of  an  ordinary  aspirating  bottle  which  may 
be  used  as  a  source  of  water  supply  by  putting  ice  into  water  and 
allowing  the  ice  water  to  flow  through  the  condenser  as  a  means 
of  cooling  the  water  vapors.  The  rest  of  the  apparatus  con- 
sists of  a  pyrex  distilling  flask  suitably  connected  to  a  glass 
condenser  with  a  flask  for  collecting  the  water.  The  whole 
apparatus  is  held  in  place  by  a  single  iron  stand  with  the  necessary 
clamps  and  rings.  The  apparatus  is  cheap  and  very  compact  as 
well  as  usable.  In  fact  it  may  be  used  by  any  physician  who 
has  need  for  distilled  water  and  has  gas  and  running  water 
available.  If  the  water  is  used  within  a  half  hour,  it  is  sterile  and 
suitable,  otherwise  it  is  necessary  to  boil  the  water  before  using 
and  then  cool  it  to  room  temperature  (68-77°  F.)  before  using 
it.  Under  no  circumstances  should  hot  water  be  used  with  sal- 
varsan  or  neosalvarsan. 

The  Drug 

In  manufacturing  arsphenamine  every  care  is  used  in  protec- 
ting the  drug  from  undue  exposure  to  oxidation  and  moisture 
and  it  is  reasonably  safe  to  say  that  the  product  is  very  uniform 
in  composition  and  therapeutic  properties.  Every  ampule  is 
carefully  examined  for  any  imperfection  by  the  flotation  method 
before  it  leaves  the  laboratory.  During  transportation  accidents 
may  happen  to  the  glass  container  and  in  every  instance  the 
ampule  should  be  placed  in  95%  alcohol  for  20  minutes,  to 
detect  any  imperfections  such  as  a  minute  crack,  which  is 
invisible  to  the  naked  eye,  and  at  the  same  time  to  sterilize  the 


46  THE  TREATMENT  OF  SYPHILIS 

ampule.    After  examination  the  ampule  is  dried  with  a  piece  of 
sterile  cotton  or  gauze. 

It  is  imperative  that  neither  the  contents  of  ampules  that 
may  have  been  damaged  in  transport,  nor  the  remainder  of 
previously  opened  ampules  should  be  used,  as  this  involves 
serious  danger  to  the  patient.  While  the  ampule  is  in  immersion, 
all  the  instruments  and  utensils  which  are  being  utilized  in  the 
administration  should  be  boiled  in  distilled  water. 

The  Solution 

Before  discussing  this  most  important  phase  of  the  technic 
in  arsphenamine  administration,  it  may  not  be  amiss  to  make 
reference  to  the  fundamental  principle  of  therapeutics.  All 
therapeutic  action  is  based  upon  the  laws  of  chemical  affinity 
which  are  in  turn  governed  by  the  laws  of  chemical  dynamics  and 
equiHbrium.  The  demands  on  the  drug  are  such  that  it  is  essen- 
tial the  number  of  reactions  should  be  reduced  to  a  minimum. 
To  meet  these  requirements  it  is  necessary  to  foUow  certain 
definite  laws  of  chemistry. 

Some  physicians  insist  on  using  the  drug  in  concentrated  solu- 
tions and  pay  little  attention  to  alkalinization.  Alkalinization 
and  concentration  are  the  two  most  important  factors  in  preparing 
the  solution  for  injection.  It  is  a  well-known  fact  that  if  solid 
sodium  hydroxid  is  dropped  into  concentrated  hydrochloric 
acid  considerable  heat  is  evolved,  due  to  chemical  action  in 
forming  the  compound  sodium  chlorid.  The  same  applies  to 
arsphenamine  when  it  is  injected  into  the  blood  stream.  A  new 
compound  is  formed,  one  in  which  the  proteins  of  the  blood 
stream  and  the  protozoa  combine  with  the  arsenical.  The 
rapidity  and  amount  of  combination  are  the  factors  which 
determine  whether  there  will  be  disturbances  in  the  host. 

The  cause  of  this  chemical  reaction  is  to  be  found  in  the  fun- 
damental laws  of  energy  changes.  All  of  the  energy  changes  are 
easily  subdivided  into  intensity  factors,  and  capacity  factors. 
The  intensity  factor  of  any  form  of  energy  or  change  tends  toward 
equalization  of  differences  which  condition  develops  when  the 


Distilling  Apparatus 

A  simple  and  inexpensive  water  still  for  physicians  who  have  laboratories 
in  connection  with  their  ofifices. 


TECHNIC  OF  ARSPHENAMINE  ADMINISTRATION        47 

rate  of  injection  is  very  slow  and  the  dilution  is  great.  When 
two  substances  are  brought  together,  the  tendency  to  equalize 
the  difference  in  concentration  and  tolerance  is  adjusted  by  the 
body.  This  can  only  be  accomplished  when  the  organism  has  an 
opportunity  to  meet  these  new  conditions  and  establish  an 
equilibrium  where  the  drug  changes  into  a  soluble  compound 
in  the  body,  making  due  allowance  for  decomposition  of  the 
arsphenamine  and  the  rate  of  elimination. 

To  all  those  familiar  with  dynamics  it  will  at  once  be  observed 
that  the  "ideal"  solution  is  the  one  which  gives  the  most  uniform 
results  chemically,  physically,  and  therapeutically.  The  con- 
centrated solutions  should  yield  abnormal  results  unless  the 
time  factor  is  so  carefully  controlled  that  an  ideal  condition  is 
obtained. 

Upon  this  scientific  basis  it  is  now  suitable  to  prepare  the 
solution. 

Preparation  of  the  Solution 

A  dilution  of  100  mg.  (o.i)  to  25  c.  c.  of  water  is  probably  with- 
in the  safe  limits.  The  United  States  Army  and  the  United 
States  PubHc  Health  Service  have  recommended  a  dilution  of 
100  mg.  in  30  c.  c.  of  water.  This  is  a  most  conservative  recom- 
mendation in  view  of  the  fact  that  there  may  be  other  abnor- 
malities existing  in  the  patients.  It  is  also  much  better  to  err 
on  the  side  of  precaution  and  conservatism.  The  size  of  the  dose 
recommended  is  generally  conceded  to  be  a  0.4  gram  dose  which 
should  be  given  more  frequently.  This  subject  will  be  discussed 
at  length  in  another  chapter. 

The  ampule  of  salvarsan  should  be  opened  by  filing  it  in  two 
or  three  places  near  the  point  where  the  body  of  the  ampule 
joins  the  tip.  A  smart  blow  on  the  end  of  the  ampule  will  break 
it  off  cleanly. 

About  50  c.  c.  of  room  temperature  (68-77°  F.)  sterile,  freshly 
distilled  water  should  be  poured  in  the  mixing  cylinder  and  the 
contents  of  0.4  gram  ampule  lightly  scattered  on  the  surface  of 
the  liquid,  using  care  in  maintaining  asepsis.  The  stopper  should 
be  placed  in  the  flask  and  gentle  agitation  follow.    The  powder 


48  THE  TREATMENT  OF  SYPHILIS 

will  dissolve  readily  in  the  cold  water  and  when  every  particle 
is  in  solution  alkali  should  be  added  at  once,  according  to  the 
table  below. 

An  ampule  of  0.4  gram  requires  3.36  c.  c.  normal  sodium  hy- 
droxide (4  per  cent)  or  16  drops  of  15  per  cent  sodium  hydroxide. 
It  is  imperative  that  the  alkali  be  free  from  carbonates  and 
gelatinous  material.  For  this  reason  it  is  best  to  use  freshly 
prepared  alkali  unless  other  proper  precautions  can  be  taken. 
Again  the  stopper  should  be  inserted  in  the  mixing  cylinder, 
which  should  be  inverted  a  couple  of  times,  and  then  the  volume 
increased  to  100  or  120  c.  c.  After  a  gentle  shaking,  if  the  proper 
care  has  been  exercised,  the  solution  will  be  ready  for  intravenous 
administration. 

The  salvarsan  solution  should  be  used  immediately.  In  warm 
weather  additional  care  should  be  used  to  avoid  imusual  tempera- 
tures. 

Table  of  Normal  and  15  Per  Cent  Sodium  Hydroxid  Necessary 

c.  c.  of  normal  NaOH     Drops  (aver.  =  .07  c.  c.) 
tn  salt       15%  NaOH  required 
for  disodium  salt 

4 
8 
12 
16 
20 
24 
28 
32 
36 
40 

The  mechanism  of  the  change  taking  place  during  the  alkaliniza- 
tion  is  shown  by  the  following  table  which  indicates  the  most 
satisfactory  form  in  which  the  drug  should  be  given. 


Weight  of  drug 

required  for  dis 

.1 

0.84 

2 

1.68 

3 

2.52 

4 

336 

5 

4.20 

6 

504 

7 

5-88 

8 

6.72 

9 

7  56 

I 

0 

8.40 

Apparatus  for  Holding  Normal  Sodium  Hydroxid  Solution 

The  solution  can  be  kept  in  the  bottle  indefinitely  and,  as  it  is  measured 
out  by  a  burette,  absolute  accuracy  is  certain,  and  perfect  alkalinization 
is  effected. 

The  box  holding  the  apparatus  is  shown  with  the  sides  and  top  turned 
back  and  the  front  cover  removed. 


TECHNIC  OF  ARSPHENAMINE  ADMINISTRATION       49 


CHEMICAL  TRANSFORMATION  OF  SALVARSAN 

INTO  THE  DISODIUM  SALT 

Required  for  Intravenous  Injection 
I    SALVARSAN 


NH,HCl        "Ns.  ^y^HHjaCl 

OH        4^^  OH  A 

Salvarsan  as  it  appears  on  market 

n    SALVARSAN  BASE 

AS  •— —"^g^ 


OH     y  OH 

Sodium  Chlorid  Na  CI  is  formed 
at  this  stage  of  alkalinization 

m     MONO-SODIUM  SALT 

OF  SALVARSAN 

A3 


DI-SODIUM  SALT 

OF  SALVARSAN 


SALVARSAN   DI-HYDROCHLORIDE. 

Yellow  Powder   about  Sl^^Arsoiic. 
Soluble  in  cold  water.; 
Add  to  litmus. 

Solution  not  suitable  for  intraveno«s 
administration. 


U 

SALVARSAN  BASE. 

Precipitated  upon  addition  of  12  drops  of 
15%  sodium  hydroxide  solution  or 

252  cc.  of  normal  sodium  hydroxide 
solution  per  0.6  gram  Salvarsan. 

Insoluble  yellow  precipitate. 
Causes  reactions. 

Not  suitable  for  intravenous  administra* 
tion. 

m 

MoNo-ScH)iuM  Salt  of  Salvarsan 

Formed  upon  addition  of  18  drops  of 
15%  sodium  hydroxide  solution  or 

3.78  cc.  normal  sodium  hydroxide  sdu- 

tion. 
JiM  soluble  in  water. 
Clear  yellow  soludcm. 
Slightly  alkcJine  to  litmus. 
Not  suitable  for  intravenous  a<bnini^m-' 

tion. 

IV 

K-S(M)IUM  SALT  OF  SALVARSAN 

Formed  upon  addition  of  24  drops  of 
15%  sodium  hydroxide  solution  or 

5.04  cc.  normal  sodiimi  hydroxide  solu- 
tion. 

Completely  soluble  in  water. 

Qear  yellow  solution. 

Ready  for  intravenous  administration  m 
dilution  of  0.1  gram  in  30cc.  of  freshly 
distilled  water. 

This  is  the  only  form  in  which  Salvar^m 
solution  should  be  used. 


50  THE  TREATMENT  OF  SYPHILIS 

Necessity  for  Proper  Alkalinization 

Some  physicians  have  a  tendency  to  discontinue  the  alkaliniza- 
tion at  the  point  where  the  precipitate  disappears  and  the  solu- 
tion becomes  clear.  This  is  a  dangerous  procedure  for  the  reason 
that  the  tendency  to  form  precipitates  is  greatly  increased  at 
this  alkalinity,  since  the  presence  of  carbonates,  carbon  dioxide, 
magnesium  and  calcium  salts  combine  more  readily  in  this 
condition  than  in  the  form  of  the  disodium  salt  (Myers,  U.  S. 
Public  Health  Reports). 

Under  these  conditions  the  precipitates  not  only  cause  me- 
chanical stoppage  in  the  capillaries,  but  also  extract  calcium  and 
magnesium  from  the  blood.  These  last  two  elements  are  neces- 
sary for  cardiac  stimulation  and  when  they  are  removed  the 
blood  pressure  obviously  falls  below  normal.  Such  a  condition 
aids  in  allowing  the  precipitates  to  collect  and  block  the  capil- 
laries. Calcium  forms  an  insoluble  salt  with  arsphenamine  and 
this  can  only  be  prevented  by  the  use  of  a  more  strongly  al- 
kalinized  solution,  namely,  the  disodium  salt.  These  facts  hold 
true  with  all  the  preparations  on  the  market  at  the  present  time. 
Arsphenamine  is  a  substance  which  tends  to  aid  blood  coagula- 
tion and  therefore  there  is  an  eminently  good  reason  for  the 
proper  administration  of  the  drug. 

D.  E.  Jackson  and  M.  I.  Smith  of  the  Hygienic  Laboratory, 
United  States  Public  Health  Service  have  shown  that  there  is 
no  perceptible  fall  in  blood  pressure  when  the  drug  is  injected  as 
it  should  be.  When  it  is  introduced  rapidly  and  in  concentrated 
solution,  the  pressure  falls  very  slowly  and  collapse  may  result. 
These  facts  tend  to  stimulate  the  manufacturer  to  keep  up  the 
high  standard  of  purity  of  the  product. 

In  the  early  history  of  the  American  manufacture  of  ar- 
sphenamine, some  products  of  poor  quality  appeared  on  the 
market  but  with  the  present  high  standards  in  force,  salvarsan 
par  excellence  is  being  produced,  having  the  advantages  of  being 
easily  soluble  in  cold  water,  of  having  a  uniformly  high  arsenic 
content,  as  well  as  possessing  the  same  therapeutic  power  of  any 
arsenical  produced  at  any  time. 


TECHNIC  OF  ARSPHENAMINE  ADMINISTRATION        51 

The  Filtering  of  the  Salvarsan  Solution  into  the  cylinder 
which  is  to  be  utilized  for  it  is  urgently  recommended.  A 
small  bit  of  glass  may  have  chipped  off  the  ampule  during  the 
filing  and  found  its  way  into  the  solution  and  extraneous  matter 
may  get  into  the  preparation  despite  the  greatest  care.  We 
advocate  the  use  of  heavy  layers  of  thoroughly  sterilized  gauze 
for  purposes  of  filtering,  rather  than  to  employ  absorbent 
cotton.  It  was  formerly  possible  to  get  a  sterilized  cotton 
which  was  satisfactory  for  purposes  of  filtration,  but  a  well- 
known  genito-urinary  surgeon  recently  traced  some  reactions 
following  salvarsan  administration  to  the  use  of  absorbent  cot- 
ton. 

Upon  chemical  analysis  he  discovered  the  presence  of  an  acid 
which  undoubtedly  caused  the  reaction.  Calcium-chloro-hypo- 
chlorite  (CaCl  0  CI),  incorrectly  called  chloride  of  lime,  and 
known  by  the  trade  name  of  bleaching  salt  of  lime,  is  used  in 
bleaching  cotton.  The  chlorite  present  in  the  cotton  was  due  to 
the  chlorine  contained  as  natural  chlorites  and  probably  to 
chloride  of  lime  remaining  in  the  cotton  due  to  incomplete  neu- 
tralization and  washing  in  the  process  of  preparation  of  the 
absorbent  cotton.  The  acid  present  was  undoubtedly  due  to  the 
formation  of  either  a  little  hydrochloric  acid  from  the  bleaching 
salt  of  lime  by  the  action  of  sulphuric  acid,  by  which  the  cotton 
is  treated  to  neutralize  the  alkalinity  of  the  bleaching  lime,  or  to 
the  presence  of  both  hydrochloric  and  sulphuric  acids. 

Physicians  using  absorbent  cotton  who  get  reactions  would 
do  well  to  make  a  chemical  analysis  of  their  cotton. 

After  filtering  the  solution  of  salvarsan  into  one  cylinder  we 
next  run  100  or  more  c.  c.  of  freshly  distilled  sterilized  water  into 
the  other  cylinder,  the  rubber  tubing  having  been  previously 
attached  to  each  cylinder.  The  tubing  should  then  be  raised 
up  and  down  a  sufficient  length  of  time  until  aU  the  bubbles  of 
air  have  disappeared.  The  tubing  can  be  squeezed  in  various 
places  so  as  to  make  certain  no  air  is  present.  The  needle 
should  be  attached  by  short  rubber  tubing  to  the  Morton  three- 
way  stopcock,  with  a  window  made  of  glass  tubing  between  the 
stopcock  and  the  needle,  so  that  when  the  puncture  is  made  the 


52  THE  TREATMENT  OF  SYPHILIS 

operator  can  ascertain  his  whereabouts  in  the  vein  by  the  back 
flow  of  blood. 

Preparation  of  the  Patient 

After  having  determined  that  there  are  no  contraindications 
to  the  administration  of  arsphenamine  or  neoarsphenamine,  the 
preparation  of  the  patient  for  treatment  should  begin  the  night 
before  the  administration,  when  an  active  catharsis  must  be 
induced.  At  the  time  of  the  injection,  the  gastrointestinal  tract 
must  be  entirely  clear.  If  the  treatment  is  to  be  given  in  the 
morning,  the  patient  should  eat  no  breakfast  and,  if  in  the  after- 
noon, no  luncheon.  We  make  it  a  rule  to  allow  no  food  in  the 
stomach  for  at  least  six  hours  before  the  injection,  thus  insuring  a 
clean  intestinal  tract.  There  is  no  objection  to  a  cup  of  weak 
tea  at  meal  time,  but  no  soUd  food  of  any  type  should  be  per- 
mitted. 

It  is  necessary  to  examine  the  urine  before  each  injection. 

When  these  details  have  been  carried  out  and  the  patient  is 
ready  for  the  administration  of  the  drug,  he  should  be  laid  in  a 
recumbent  position  on  a  surgical  table  or,  if  the  injection  is  given 
at  home,  on  a  bed.  If  the  surgical  table  is  used,  it  is  very  easy  to 
affix  an  arm  thereto,  upon  which  the  patient's  arm  can  rest. 
This  gives  the  operator  the  advantage  of  having  the  field  of 
operation  perfectly  steady  at  all  times. 

The  Choice  of  the  Vein 

The  vein  of  choice  is  the  cephalic  just  below  the  jimction  with 
the  vena  mediana  cubiti,  as  at  this  place  a  level  spot  is  offered, 
whereas  a  little  higher  up  the  bend  of  the  elbow  is  encountered 
with  its  attendant  inconvenience  for  the  entrance  of  the  needle. 
If  for  any  reason  this  vein  is  not  available,  the  basilic,  just  above 
or  below  the  junction  with  the  median  antibrachial,  offers  the 
most  attractive  site  of  entrance. 

Sometimes  the  accessory  cephalic  is  large  enough  for  the  easy 
insertion  of  a  needle  and  as  a  dernier  ressort  the  physician  is  some- 
times compelled  to  use  the  median  antibrachial  near  the  wrist  or 
one  of  the  oblique  branches  connecting  the  basilic  and  cephalic. 


54  THE  TREATMENT  OF  SYPHILIS 

the  needle  squarely  in  the  vein,  the  tourniquet  should  be  released 
and  the  rubber  tubing  attached.  The  stopcock  is  then  opened  to 
permit  the  entrance  of  about  25  c.  c.  of  distilled  water  into  the 
vein. 

The  Introduction  of  Distilled  Water  before  the  Arsphenamine 

The  purpose  of  the  introduction  of  the  distilled  water  first 
is  that  if  there  should  be  any  leaking  around  the  point  of  entrance 
caused  by  the  tearing  of  the  vein  the  use  of  distilled  water  will 
obviate  any  pain,  or  possible  inflammation  caused  by  infiltra- 
tion. The  arsphenamine  solution,  if  allowed  to  leak  out,  would 
cause  a  burning  sensation  and  considerable  difficulty  might  re- 
sult from  an  infiltration.  After  the  injection  of  25  c.  c.  of  dis- 
tilled water  the  stopcock  is  turned  and  the  salvarsan  introduced 
very  slowly,  the  operator  allowing  at  least  two  minutes  for  each 
decigram  of  salvarsan.  When  the  full  amount  has  been  injected, 
he  should  switch  back  to  the  distilled  water  and  thus  wash  out 
the  vein. 

After  the  needle  has  been  removed  it  is  better  for  the  patient 
to  hold  his  hand  perpendicularly  for  a  short  time,  pressing  a 
pledget  of  sterile  gauze  over  the  point  of  entrance.  When  the 
bleeding  has  entirely  stopped  a  drop  of  collodion  should  be  placed 
over  the  point.    There  is  no  necessity  to  bandage  the  arm. 

The  patient  should  be  kept  in  a  recumbent  position  for  from 
fifteen  minutes  to  an  hour  and  he  should  remain  quiet  the  re- 
mainder of  the  day.  We  have  given  in  our  office  many  injections 
of  salvarsan  to  patients  who  have  gone  long  distances — some  as 
far  as  one  hundred  miles — within  an  hour  after  the  injection. 
This  practice  is  not  recommended,  however,  and  is  only  advisable 
in  times  of  emergency.  As  reactions  may  follow  several  hours 
after  the  injection  it  is  always  well  to  have  the  patient  near  at 
hand. 

Helpful  Hints  in  Treatment 

There  are  many  small  points  in  connection  with  the  injection  of 
arsphenamine  which,  if  carried  out,  are  helpful.  One  of  the  first 
is  the  use  of  sharp  needles.     We  suggest  a  very  sharp,  short- 


TECHNIC  OF  ARSPHENAMINE  ADMINISTRATION        55 

beveled  needle  instead  of  one  with  a  long  sharp  point,  as  the  long- 
pointed  type  may  catch  in  the  wall  of  the  vein  and  cause  a 
leak.  A  dull  needle  is  not  only  likely  to  tear  the  vein  and  cause 
subsequent  infiltration,  but  the  pain  attendant  upon  its  use  is 
discouraging  to  the  patient.  The  use  of  such  a  needle  is  partic- 
ularly difficult  when  the  patient  happens  to  be  of  a  neurotic  type. 

If  the  veins  do  not  stand  out  perfectly  with  the  application 
of  the  tourniquet,  a  few  smart  slaps  on  the  arm  over  the  intended 
point  of  entrance  will  often  have  the  desired  effect.  Another 
method  of  enlarging  the  vein  is  to  have  the  patient,  with  his  arm 
very  rigid,  bend  his  wrist  forward  so  that  the  clenched  first  will 
be  at  an  angle  of  45°  to  the  forearm. 

Some  small  veins  can  be  brought  out  by  the  application  of 
sterile  gauze  wrung  out  in  hot  water. 

Walking  up  three  or  four  flights  of  stairs  or  bending  over  and 
touching  the  floor  with  the  fingers^  without  flexing  the  knees, 
are  also  recommended  for  bringing  out  the  veins. 

In  injecting  a  vein,  if  for  any  reason  the  blood  does  not  flow 
freely  and  the  operator  desires  to  use  the  same  vein  higher  up  it 
is  well  to  leave  the  first  needle  in  place  and  make  the  injection 
through  another  needle,  as  by  the  removal  of  the  first  needle  a 
hematoma  may  result. 

We  desire  to  warn  particularly  against  using  the  stylet  of  the 
needle  to  cleanse  a  needle  which  may  seem  to  be  clogged  up. 
An  embolism  is  likely  to  follow  such  prodecure. 

Too  rapid  injection  of  salvarsan  may  bring  about  a  feeling  of 
dyspnea  and  oppression,  due  to  the  over-dilution  of  the  blood  in 
the  right  heart,  with  the  result  that  the  blood  going  into  the 
lungs  contains  an  insufficient  amount  of  oxygen. 

At  times  it  is  not  possible  to  have  an  assistant  when  administer- 
ing salvarsan  and  the  removal  of  the  tourniquet  may  prove  some- 
what awkward  to  the  operator.  The  patient,  if  a  man,  can  very 
easily  be  taught  to  grasp  his  undershirt  or,  if  he  wears  the  sleeve- 
less type,  the  outside  shirt  in  one  finger  and  roll  it  up  so  tightly 
that  the  circulation  will  be  completely  impeded.  This  makes 
a  most  efficient  tourniquet  and  can  be  released  upon  a  word  from 
the  physician. 


56  THE  TREATMENT  OF  SYPHILIS 

The  Use  of  Vasodilators 

Dr.  George  E.  Barnes  of  Herkimer,  N.  Y.  {Boston  Medical  &* 
Surgical  Journal,  May  15,  1919),  offers  an  ingenious  method  for 
facilitating  the  insertion  of  the  needle  into  small  veins  by  the 
use  of  vasodilators.  He  recommends  nitroglycerin  as  the  par- 
ticular product  to  be  used.  Barnes  believes  that,  while  this 
acts  acutely,  there  is  also  good  reason  to  use  other  remedies  for 
a  continual  state  of  normal  tension  of  the  vessels  and  suggests 
such  products  as  gelsemium,  cannabis,  Pulsatilla,  conium,  lu- 
pulin,  cramp  bark  and  cactus.  He  suggests  that  the  nitro- 
glycerin be  taken  in  the  proper  dosage  in  tablet  form,  chewed  up, 
dissolved  in  the  saliva  and  swallowed.  Such  a  drug,  however, 
should  not  be  used  until  it  is  ascertained  whether  or  not  the 
patient  is  likely  to  have  a  reaction. 

A  Window  over  the  Vein 

Dr.  E.  G.  Ballenger,  of  Atlanta  {Genito-Urinary  Diseases  and 
Syphilis,  p.  477,  1913)  has  a  unique  method  of  inserting  a 
needle  itito  a  vein  which  is  not  easily  palpable  or  visible.  By 
means  of  a  small  round  stiletto  he  had  fashioned  for  the  pur- 
pose, a  window  is  made  in  the  skin  over  the  vein,  the  skin  first 
being  pulled  to  one  side,  so  that  the  stiletto  will  not  injure  the 
vein.  This  leaves  a  window  twice  the  size  of  the  needle  directly 
over  the  vein.  With  the  vein  well  distended  and  often  visible 
through  the  hole,  it  is  easy  to  slip  the  needle  through  the  opening 
directly  into  the  vessel. 

Concentrated  Injections  of  Arsphenamine 

Some  men  of  great  eminence  are  utilizing  salvarsan  in  the 
concentrated  method.  Dr.  E.  L.  Keyes,  Jr.,  in  his  splendid  book 
on  Urology  observes,  page  827,  that  "the  original  technic  calls 
for  the  administration  of  300  c.  c.  of  fluid.  At  present  the  usual 
allowance  is  10  c.  c.  of  distilled  water  for  every  decigram  of  the 
drug  to  be  injected.  The  dose  for  the  adult  male  is  three  or 
four  decigrams;  for  the  adult  woman,  three  decigrams;  for  the 
infant,  one  centigram.  .  .  . 


2  ^ 


■5  2 

^  2 


> 
q 

C3 

2i 

1^ 

c 

rrl 

t 

rt 

^ 

w 

[^ 

-c 

w 

QJ 

PL, 

-— ^ 

< 

P^ 

c 

<U 

o 

ki 

5r 

> 

«J 

o 

4-1 

y-\ 

XI 

aj 

X 

U 

M 

f^ 

^ 

c 

o 

1— 1 

t2 

O 

3 

;S 

I? 

M 

O 

^/J 

c 

> 

S 

^ 

_g 

H 

fi 

OJ 

?; 

rt 

J=! 

1— 1 

o 

U, 

■55 

Hi 

c 

OJ 

^ 

-C 

*-f-* 

1) 

-o 

rt 

0 

4J 

n 

r, 

0 

0 

3 

t/i 

TI 

-^ 

, 

0 

H 

cr 

TECHNIC  OF  ARSPHENAMINE  ADMINISTRATION        57 

"The  injection  is  made  either  by  gravity  or  with  a  30  c.  c. 
piston  syringe  or  by  a  syringe  to  which  is  attached  a  three-way 
stopcock  and  one  rubber  tube  leading  into  the  bottle  containing 
the  salvarsan,  while  the  other  leads  to  the  needle  in  the  patient's 
arm.  Whatever  the  method  employed,  it  is  essential  that  the 
salvarsan  be  given  slowly  and  that  at  least  five  and  preferably 
ten  minutes  be  taken  for  the  injection  of  the  30  c.  c.  Therefore, 
the  gravity  method  is  the  safest." 

The  concentrated  method  of  salvarsan  introduction  is  doubt- 
less a  safe  one  in  the  hands  of  so  experienced  and  skillful  an 
operator  as  Dr.  Keyes,  but  for  the  average  medical  man,  part 
of  whose  time  must  necessarily  be  given  to  other  lines  of  medicine, 
we  feel  that  the  concentrated  method  is  unsafe.  Dr.  Keyes' 
technic  is  presented  to  show  that  the  concentration  of  the  fluid 
is  not  regarded  as  dangerous  by  one  of  our  most  eminent  col- 
leagues, but  the  earnest  suggestion  is  made  that  men  who  have 
not  had  as  much  experience  in  the  administration  of  salvarsan 
as  Dr.  Keyes  do  not  emulate  his  example. 

Dr.  Theodore  H.  Smith,  of  Detroit  {Jour.  Mich.  State  Med. 
Soc,  April,  191 7)  believes  that  concentrated  solutions  of  sal- 
varsan are  more  effective  than  dilute  ones  in  that  the  salvarsan 
in  the  concentrated  solution  is  more  slowly  excreted,  but  he  ad- 
mits that  the  one  objection  to  this  method  is  the  urgent  necessity 
of  a  perfect  technic  in  the  intravenous  injection  itself.  He  says 
that  if  the  needle  does  not  lie  accurately  within  the  vein,  a  small 
amount  of  the  concentrated  solution  entering  the  perivascular 
tissue  will  produce  results  even  more  dangerous  than  with  the 
more  dilute  solution. 

Injection  of  Salvarsan  into  the  Superior  Longitudinal  Sinus 

One  of  the  largest  venous  channels  in  the  body  is  the  longi- 
tudinal sinus  lying  at  the  posterior  angle  of  the  anterior  fontanel. 
Through  this  medium  salvarsan  can  be  injected.  It  has  been 
used  for  a  number  of  years  for  the  injection  of  saline  solutions  and 
for  blood  transfusion. 

Dr.  Louis  Fischer  of  New  York,  read  a  paper  on  "The  Value 
of  the  Longitudinal  Sinus  in  Transfusion  and  for  Rapid  Medica- 


58  THE  TREATMENT  OF  SYPHILIS 

tion"  before  the  Section  on  Diseases  of  Children  of  the  American 
Medical  Association  in  June,  1918.  He  expressed  himself  as 
thoroughly  convinced  that  the  difficulty  of  entering  a  vein  the 
size  of  the  median  basilic  or  even  the  femoral,  in  infancy,  makes 
the  longitudinal  sinus  the  route  of  choice  for  the  introduction  of 
any  medication  into  the  system  of  an  infant  or  for  transfusion. 

Dr.  Fischer  has  perfected  a  technic  which  physicians  can  well 
follow.  He  wraps  the  infant  in  a  mummy  bandage,  well  pinned, 
so  that  the  arms  and  legs  are  confined,  and  places  the  child  flat 
on  its  back.  The  head  is  steadied  on  both  sides  by  an  assistant 
while  the  needle  is  inserted  into  the  sinus.  He  finds  that  he  can 
enter  through  the  anterior  fontanel  until  the  child  has  reached 
the  end  of  its  second  year.  As  the  sinus  grows  wider  toward  the 
back  of  the  head,  Fischer  recommends  the  point  of  entrance  to 
be  as  far  posterior  as  possible. 

The  needle  is  pushed  through  the  posterior  angle  of  the  fon- 
tanel and  directed  downward  and  backward  in  a  line  with  the 
sagittal  suture.  The  sinus  is  very  superficial  and  there  is  no 
need  of  entering  deeper  than  i  or  2  mm.  For  this  purpose  a 
sharp-pointed  needle  3^  inch  long  of  20  or  22  gauge  is  best 
adapted.  When  the  needle  penetrates  the  sinus,  resistance  is 
lessened  and  the  same  sensation  is  observed  as  when  a  needle 
enters  the  dura  mater  in  performing  a  lumbar  puncture. 

In  giving  salvarsan  by  this  method.  Dr.  Fischer  advises  that 
it  be  administered  by  gravity  slowly.  A  cylinder  from  30  to 
100  c.  c.  capacity  can  be  used.  One  end  of  a  piece  of  rubber 
tubing  is  attached  to  the  cylinder  and  the  other  end  has  a  con- 
necting tip  which  fits  into  the  needle.  A  stopcock  should  be  at 
the  end  of  the  cylinder  or  near  the  end  of  the  tubing.  The 
needle  is  inserted  into  a  small  syringe  attached.  By  a  slight 
aspiration  the  physician  can  determine  whether  the  sinus  has 
been  entered;  if  so,  the  syringe  is  detached  and  the  apparatus, 
which  has  been  filled  and  the  air  expelled,  is  connected. 

The  child  should  be  watched  carefully  and  its  color,  pulse  and 
respiration  noted. 

Dr.  Fischer  is  of  the  opinion  that  there  is  no  danger  of  losing  too 
much  blood  by  the  puncture,  even  though  a  large  needle  is  used. 


TECHNIC  OF  ARSPHENAMINE  ADMINISTRATION        59 

Dr.  Vincent  of  Boston  warns  against  injecting  too  rapidly 
lest  increase  of  intra-cranial  pressure  cause  vomiting  and  dis- 
turbed respiration.  These  difficulties  are  soon  overcome  when 
the  flow  of  blood  has  been  temporarily  checked.  Air  pressure  in 
the  tube  must  be  released  by  detaching  the  syringe  before  the 
needle  is  withdrawn. 

Blood  Precipitates 

Danysz  and  Fleig  have  written  extensively  about  the  forma- 
tion of  precipitates  when  salvarsan  is  introduced  into  the  blood 
by  the  intravenous  route.  The  cause  of  many  reactions  has 
been  traced  to  the  use  of  acid  and  under-alkalinized  solutions. 

Herring  {Munch  Med.  Woch.,  Vol.  57,  No.  50, 191 1)  has  shown 
that  in  rabbits  the  acid  solution  is  twenty  times  as  toxic  and  in 
dogs  ten  times  as  toxic  as  a  properly  alkalinized  solution.  When 
an  acid  solution  is  introduced  into  the  blood  stream  a  yellow, 
insoluble  precipitate  is  formed  and  this  prevents  the  flow  of  the 
blood  through  the  capillaries.  In  this  condition  calcium  and 
magnesium  are  precipitated  as  insoluble  salts  of  salvarsan.  The 
removal  of  these  elements  from  the  blood  stream  has  a  tendency 
to  reduce  the  blood  pressure  and  in  the  presence  of  the  insoluble 
blood  precipitate,  it  is  practically  impossible  for  the  blood  to 
circulate  through  the  capillaries. 

If  a  properly  alkalinized  solution  (disodium  salt)  is  used,  no 
fall  in  blood  pressure  is  observed  and,  in  addition,  the  formation 
of  precipitates  is  almost  entirely  eliminated.  If  the  monosodium 
salt  is  used,  the  carbonates,  sulphates  and  alkaline  phosphates 
cause  a  precipitation  of  the  drug  very  easily  on  account  of  the 
hydrogen  ion  concentration,  resulting  from  the  chemical  com- 
binations. An  alkahne  solution  (many  hydroxyl  ions)  tends  to 
ehminate  these  conditions.  The  isolation  and  chemical  analysis 
of  these  blood  precipitates  will  be  found  in  a  recent  U.  S.  Public 
Health  report. 

The  Intramuscular  Administration  of  Arsphenamine 

The  intramuscular  method  of  injection  was  in  the  early  days  of 
salvarsan  hailed  as  an  easy  and  convenient  manner  of  introducing 


6o 


THE  TREATMENT  OF  SYPHILIS 


the  drug  into  the  system.  The  pain  attendant  upon  the  injection 
proved  to  be  a  raison  d'etre  for  discarding  the  method  in  favor 
of  intravenous  medication  on  the  part  of  the  great  majority  of 
salvarsan  users.  The  intramusular  method  is  still  employed  in 
such  cases  as  present  no  suitable  veins,  and  again  by  physicians 
who  believe  the  results  from  the  intramuscular  method  excel 
those  from  intravenous  introduction. 

Col.  Charles  F.  Craig,  U.  S.  Army  {The  Wassermann  Test, 
p.  1 80,  1 9 18)  has  demonstrated  the  truth  of  this  assertion  by  a 
study  of  500  cases,  of  which  209  were  treated  by  the  intramus- 
cular injection  of  the  alkaline  solution,  249  by  the  intravenous 
injection  of  the  drug,  and  42  by  combined  intramuscular  and 
intravenous  injections. 

This  table  illustrates  the  effect  of  the  method  of  administra- 
tion upon  the  Wassermann  reaction: 


Method  of 

Total 
Cases 

Became  Negative 

Remained  Positive 

Administration 

Number 

% 

Number 

% 

Intramuscular.  . . . 

Intravenous 

Combined 

209 

249 

42 

159 

lOI 

28 

76.0 

44-5 
66.6 

50 

148 

14 

24 

55-5 

2,3-3, 

Totals 

500 

288 

57.6 

212 

42.4 

It  will  be  observed,  from  a  study  of  the  table,  that  the  effect 
of  intramuscular  injections  of  salvarsan  upon  the  reaction  is 
much  more  pronounced  than  other  methods  of  administration. 
This  method  of  administration  has  been  almost  abandoned  by 
the  profession,  and  in  the  army  it  has  been  entirely  replaced  by 
the  intravenous  method,  owing  to  the  pain  and  complications 
that  follow  the  injections  and  the  time  lost  in  hospital.  However, 
there  is  no  question  in  Craig's  opinion  that  the  intramuscular 
method  is  infinitely  more  efficient  in  treatment  than  the  in- 
travenous, as  shown  by  the  results  upon  the  Wassermann  test, 
for  of  the  209  cases  so  treated,  most  of  them  receiving  but  one 
injection  of  0.6  gram  salvarsan,  159,  or  76  per  cent  became  nega- 


TECHNIC  OF  ARSPHENAMINE  ADMINISTRATION        6i 

tive,  and  fewer  cases  treated  by  the  intramuscular  method  re- 
lapsed than  when  treated  mtravenously. 

The  figures  given  for  the  intravenous  method  are  below  what 
they  should  be  for  the  reason  that  the  majority  of  the  cases 
studied  only  received  one  intravenous  injection.  Further 
observations  upon  this  method  of  administration  and  its  effect 
upon  the  Wassermann  reaction  have  shown  that  with  from 
three  to  five  intravenous  injections  the  results  are  as  good  as 
those  obtained  with  the  intramuscular  injections,  but  the  data 
here  given  are  sufficient  to  show  that  the  Wassermann  reaction 
can  be  rendered  negative  by  only  one  intravenous  injection  in  at 
least  40  per  cent  of  the  cases. 

Intramuscular  Method  Superior  to  the  Combined 

The  effect  upon  the  reaction  of  the  combined  intransmuscular 
and  intravenous  method  of  using  salvarsan  was  determined  in 
42  cases,  of  which  66  per  cent  became  negative,  thus  indicating 
that  the  results  were  not  as  good  with  the  combined  method  as 
with  the  intramuscular  method  alone.  However,  this  result  was 
due  to  the  fact  that  a  number  of  the  intramuscular  cases  had  two 
or  even  three  injections  of  salvarsan,  and  it  is  considered  that  one 
intramuscular  injection  of  the  drug  is  equal  to  at  least  three 
intravenous  injections  so  far  as  the  effect  upon  the  Wassermann 
test  is  concerned. 

As  should  be  expected,  the  effect  of  treatment  with  salvarsan 
upon  the  reaction  increases  with  the  number  of  doses  of  the  drug 
that  are  administered,  regardless  of  the  method  of  administra- 
tion. Of  200  cases  receiving  one  intramuscular  injection  of  sal- 
varsan of  0.6  gm.,  152,  or  76  per  cent  became  negative,  while  of 
9  cases  receiving  two  intramuscular  injections,  7,  or  77,7  per 
cent  became  negative.  There  is  httle  difference  between  these 
two  groups  of  cases  so  far  as  the  apparent  effect  upon  the  Wasser- 
mann test  is  concerned,  but  the  number  of  cases  receiving  two 
intramuscular  injections  is  too  small  to  allow  of  our  basing  upon 
them  any  accurate  statistics,  as  a  large  number  of  cases  would 
undoubtedly  give  a  higher  percentage  in  this  class  of  cases. 

Of  the  cases  treated  by  the  intravenous  method,  177  were 


62  THE  TREATMENT  OF  SYPHILIS 

given  one  intravenous  injection  of  0.6  gm.  of  salvarsan,  and  72, 
or  40.6  per  cent  became  negative;  52  were  given  two  intravenous 
injections  of  the  same  dose,  of  which  22,  or  42.3  per  cent  became 
negative;  while  10  cases  were  given  three  intravenous  injections, 
of  which  7,  or  70  per  cent  became  negative.  There  was  but  little 
difference  in  the  percentage  of  negative  results  obtained  in  those 
given  one  and  two  intravenous  injections;  and  it  will  be  noted  that 
two  intravenous  injections  did  not  have  as  much  effect  upon  the 
Wassermann  reaction,  as  one  intramuscular  injection.  The  per- 
centage of  negative  results  obtained  with  three  intravenous  in- 
jections, however,  approaches  closely  to  that  obtained  with  one 
intramuscular  injection,  and  justifies  the  assertion,  based  upon 
this  obvious  experience,  that  one  intramuscular  injection  is 
equal,  in  its  effect  upon  the  Wassermann  reaction,  to  three  in- 
travenous injections  of  a  salvarsan. 

Preparation  of  Arsphenamine  for  Intramuscular  Use 

Several  methods  of  preparing  salvarsan  for  intramuscular  in- 
jection are  in  vogue. 

EhrUch  set  forth  the  following  method  for  the  preparation  of 
alkaline  solutions  for  both  intramuscular  and  intravenous  in- 
jection: 

Ehrlich's  Method 

"Into  a  narrow-necked,  glass-stoppered,  sterile,  graduated 
glass  cylinder  of  300  c.  c.  capacity,  30  to  40  c.  c.  sterile  freshly  dis- 
tilled water  of  not  more  than  room  temperature  are  measured.  The 
salvarsan,  for  example  0.5  gram,  is  sprinkled  on  the  surface  of 
the  water  and  dissolved  by  vigorous  agitation.  To  the  solution, 
after  it  has  become  absolutely  clear  and  no  undissolved  particles 
can  be  seen,  19  drops  of  15%  sodium  hydroxid  solution  are 
added  by  means  of  a  pipette,  drop  by  drop.  This  causes  a  pre- 
cipitate which  dissolves  on  shaking.  The  clear  yellow  solution 
is  now  filled  up  to  250  c.  c.  with  sterile  0.5%  saline  solution  pre- 
pared from  chemically  pure  sodium  chlorid  and  sterile  Freshly 
distilled  water. 

"  Salvarsan  solutions  must  always  be  freshly  prepared.    In  the 


TECHNIC  OF  ARSPHENAMINE  ADMINISTRATION        63 

preparation  of  the  alkaline  solution  it  is  imperative  to  observe 
that  the  salvarsan  must  be  completely  dissolved  in  distilled  water 
{not  saline  solution),  at  ordinary  temperature  and  that  the  solu- 
tion does  not  show  any  gelatinous  particles  whatever  before 
the  sodium  hydroxid  solution  is  added.  The  sodium  hydroxid 
solution  is  not  added  gradually,  but  at  once.  The  precipitate 
produced  thereby  must  be  completely  dissolved  prior  to  the 
further  dilution  of  the  alkaline  concentrated  salvarsan  solution 
with  0.5%  saline  solution.  The  sodium  chlorid  must  be 
chemically  pure.  Tap  or  spring  water  is  imsuitable.  Hot  water 
must  NOT  be  used  in  preparing  the  solution  of  salvarsan.  Should 
the  solution  not  be  quite  clear  or  become  slightly  turbid  after 
a  few  minutes,  a  few  more  drops  of  sodium  hydroxid  solution 
should  be  added,  a  drop  at  a  time  and  waiting  2  or  3  minutes 
after  each  drop  to  see  if  this  quantity  suffices  to  clear  the  solu- 
tion.   Each  50  c.  c.  of  this  solution  contains  o.  i  gram  salvarsan. 

"If  no  graduated  glass  cylinder  is  at  hand,  the  concentrated 
salvarsan  solution  may  be  prepared  in  a  small  glass-stoppered 
flask,  and  after  the  addition  of  sodium  hydroxid  solution  and 
complete  clarification,  poured  into  the  saline  solution.  The  solu- 
tion should  be  filtered  if  necessary. 

"  Intramuscular  Injections  may  be  made  with  the  alkaline 
solution  as  above  described,  but  in  this  case  only  about  5  c.  c.  of 
fluid  are  required.  For  its  preparation  one  proceeds  by  well 
triturating  in  a  sterile  mortar,  for  instance  0.5  gram  salvarsan 
with  19  drops  of  15%  sodium  hydroxid  solution  and  then  dilut- 
ing with  distilled  water  to  the  desired  volume.  The  injection 
is  made  into  the  upper  exterior  sections  of  the  gluteal  muscles. 
The  injection  should  be  made  deeply  but  very  slowly,  so  as  not  to 
cause  hemorrhage.  The  neighborhood  of  the  sciatic  nerve  must 
be  carefully  avoided.  Intramuscular  injections  may  also  be 
made  with  simple  triturations  of  salvarsan  in  fatty  oils  1:10 
(Oleum  Amygdal.  dulc,  Oleimi  Sesami,  Oleum  OHvae). 

"In  all  cases  the  area  of  the  injection  must  be  previously  dis- 
infected with  iodin-benzene  or  tincture  of  iodin.  After  intra- 
muscular appUcation  the  injected  fluid  should  be  distributed  by 
massage. 


64  THE  TREATMENT  OF  SYPHILIS 

"In  sensitive  persons  the  site  of  injection  may  be  com- 
pletely anesthetized  by  a  previous  injection  of  2  c.  c.  of  a  i% 
novocain  solution.  Hydropathic  measures,  as  moist  compresses, 
hip-baths,  etc.,  or  the  appHcation  of  warm  compresses,  may  be 
successfully  employed  to  prevent  afterpain.  The  internal  ad- 
ministration of  pyramidon  has  proved  very  efficacious." 

The  Alt  Method 
The  Alt  alkaline  solution  method  is:  "Ten  c,  c.  of  sterile  dis- 
tilled water  are  placed  in  a  beaker  of  about  50  c.  c.  capacity, 
the  salvarsan  added  and  triturated  with  a  glass  rod  until  com- 
pletely dissolved.  Normal  (4  per  cent.)  sodium  hydroxid  solu- 
tion is  now  added  in  the  proportion  of  0.5  c.  c.  to  each  o.i  gram 
of  the  drug.  The  stirring  is  continued  until  a  precipitate  is 
formed  and  is  partially  redissolved.  The  alkali  solution  is  now 
added  drop  by  drop  untU  the  opacity  nearly  clears.  It  is  not 
desirable  to  permit  the  solution  to  become  completely  clear,  as 
such  a  solution  is  more  irritating  to  the  tissues  than  the  shghtly 
tubid  solution.    The  total  volume  is  now  made  up  to  20  c.  c." 

The  Michaelis  Method 

The  neutral  suspension  of  Michaelis  is  prepared  as  follows: 
"The  salvarsan  is  dissolved  in  a  solution  prepared  by  adding 
0.3  to  0.6  gram  of  sodium  hydrochlorate  to  16  c.  c.  of  very  hot 
sterile  distiUed  water  in  a  wide-mouthed  graduated  cylinder. 
From  3  to  5  c.  c.  of  normal  sodium  hydroxid  solution  are  added 
and  the  mixture  thoroughly  stirred.  Three  drops  of  a  0.5  per 
cent,  solution  of  phenolphthalein  in  70  per  cent,  alcohol  are 
added  as  an  indicator,  which  causes  a  red  color  to  develop.  Then 
I  per  cent  acetic  acid  solution  is  added,  drop  by  drop,  until  the 
red  color  disappears.  The  salvarsan  is  precipitated  as  fine  yellow 
floculi  and  finally  a  few  drops  of  the  normal  sodium  hydroxid 
solution  are  added  to  recolor  slightly  the  phenolphthalein.  The 
solution  is  then  ready  for  injection." 

Oily  Emulsions 

Oily  emulsions  are  also  employed  intramuscularly  to  advan- 
tage.   The  firm  of  Hynson,  Westcott  &  Dunning,  of  Baltimore, 


TECHNIC  OF  ARSPHENAMINE  ADMINISTRATION        65 

puts  out  ampules  of  salvarsan  in  oil  ready  for  injection,  which 
have  met  with  favor  at  the  hands  of  advocates  of  intramuscular 
medication. 

British  Army  Method 

Lt.  Colonel  L.  W.  Harrison,  R.  A.  M.  C,  in  charge  of  the  Mili- 
tary Hospital,  Rochester  Row,  England,  reports  favorably 
{Brit.  M.  /.,  May  5, 191 7)  on  the  use  of  the  intramuscular  method 
of  neosalvarsan  administration.  He  used  neosalvarsan  dissolved 
in  10-15  minims  of  distilled  water  and  injected  into  the  gluteus 
medius  muscle.  This  gave  a  fair  amount  of  pain  with  some  lame- 
ness after,  but  when  accompanied  by  a  hypodermic  injection  of 
morphin  it  proved  as  comfortable  as  any  other  method.  He  also 
utilized  the  same  amount  in  deep  subcutaneous  injection,  made 
under  the  fascia  covering  the  gluteus  medius  muscle.  This  was 
less  painful  immediately  afterward,  but  often  caused  the  forma- 
tion of  a  tender  lump  on  the  site  of  the  injection  some  days  later. 

Another  method  was  the  intramuscular  and  deep  cutaneous 
injections  of  neosalvarsan  emulsified  in  creo.  camph.,  melting 
point,  20°  C.  There  was  some  pain  for  a  few  hours  afterward  but 
as  a  rule  the  patient  would  allow  the  site  of  the  injection  to  be 
massaged  vigorously  the  following  days. 

The  most  useful  method  was  the  injection  of  six  decigrams 
neosalvarsan  dissolved  in  i  c.  c.  of  a  4  per  cent,  solution  of  sto- 
vain  and  made  up  to  2  c.  c.  with  creo.  camph.,  melting  point, 
15°  C,  or  with  camph.  phenique.  This  was  the  most  comfortable 
injection  to  use.  It  was  made  about  a  point  three  finger  breadths 
below  the  crest  of  the  ilium  on  a  line  joining  the  tuber  ischii  with 
the  point  on  the  crest  of  the  ilium,  which  is  perpendicularly  above 
the  great  trochanter,  when  the  patient  is  upright. 

As  a  result  of  these  injections,  Harrison  feels  that  the  intra- 
muscular or  subcutaneous  method  is  superior  in  immediate 
therapeutic  effect  to  the  intravenous,  that  the  spirochetes  dis- 
appear from  syphiKtic  lesions  just  as  rapidly  after  the  first  in- 
tramuscular as  after  the  first  intravenous  injection,  and  that  the 
Wassermann  reaction  is  more  quickly  influenced. 


66  THE  TREATMENT  OF  SYPHILIS 

An  American  Method 

Still  another  method  which  has  been  successfully  utilized  by 
some  American  physicians  is  to  mix  i  oz.  each  of  a  2  per  cent 
novocain  solution  and  chemically  pure  glycerin.  To  4  c.  c.  of 
this  combined  mixture  are  added  the  contents  of  an  ampule  of 
neosalvarsan.  They  are  thoroughly  mixed  together,  antisepti- 
cally  of  course,  and  i  c.  c.  is  injected  through  each  of  four  needles 
— two  in  each  buttock.  By  the  utilization  of  the  four  needles, 
there  is  not  so  much  foreign  substance  in  the  given  parts  of  the 
muscle  and  there  seems  to  be  less  likelihood  of  trouble.  The 
novocain  anesthetizes  the  part  for  some  time  and  takes  away 
the  initial  sting  of  the  injection. 

After  Treatment 

In  England  and  on  the  Continent  it  is  the  habit,  after  giving 
an  intramuscular  injection,  to  cover  the  surrounding  parts  with 
sterilized  absorbent  cotton  fixed  with  elastic  collodion.  The 
patients  were  instructed  to  rest  in  bed  for  twenty-four  hours  and, 
according  to  various  reports,  the  majority  of  them  complained 
only  of  stiffness  in  the  hip  and  thigh  and  occasionally  of  pain  in  the 
lower  extremity. 

Some  physicians  also  utilize  a  clay  dressing,  like  antiphlogistine, 
in  place  of  cotton.  It  is  their  custom  to  cover  the  entire  gluteal 
surface  with  a  thick  layer  of  properly  heated  antiphlogistine  and 
to  cover  this  with  gauze,  and  over  that  absorbent  cotton.  This 
application  seems  to  work  well  following  the  intramuscular  in- 
jection and,  not  only  aids  in  the  prevention  of  pain  and  to  a  con- 
siderable extent  prevents  any  abscess  formation,  but  enables  the 
patient  to  attend  to  his  ordinary  affairs. 

Intramuscular  Methods  not  Popular 

Notwithstanding  the  experience  of  Col.  Harrison,  as  above 
recounted,  the  vast  majority  of  practitioners  seem  to  prefer  the 
intravenous  procedure  of  administering  salvarsan  and  neosal- 
varsan. Their  reasons  are  based  upon  the  fact  that  the  local 
disturbances,  accompanied  by  pain  and  possible  abscess,  when 


TECHNIC  OF  ARSPHENAMINE  ADMINISTRATION        67 

the  intramuscular  method  is  employed,  seem  like  a  needless 
punishment  of  the  patient.  Moreover,  the  patients  themselves 
demur  and  express  a  preference  for  any  treatment  which  will 
eliminate  the  suffering  so  commonly  accompanying  the  intra- 
muscular introduction  of  arsenical  products. 

Administration  of  Arsphenamine  by  the  Rectum 

More  or  less  has  appeared  in  the  medical  press  concerning  the 
introduction  of  salvarsan  into  the  system  by  way  of  the  large 
intestine.  Various  means  have  been  advocated  for  the  introduc- 
tion of  salvarsan  in  this  manner.  This  method  is  not  advocated 
by  medical  writers  except  in  children  and  adults  whose  veins  are 
exceedingly  difficult  of  entrance.  We  have  employed  it  with 
success  in  different  individuals,  whose  veins  have  not  been  utiliz- 
able. 

The  patient  has  the  usual  pre-salvarsan  preparation,  so  far 
as  the  gastrointestinal  tract,  etc.,  is  concerned.  In  addition  the 
lower  bowel  must  be  thoroughly  cleansed  by  an  enema.  The 
patient  is  then  placed  on  the  table  in  the  Sims  or  genupectoral 
position  and  a  sterilized  catheter  is  inserted  into  the  rectum  a 
distance  of  six  inches. 

Our  technic  has  been  to  slowly  and  carefully  emulsify  salvarsan 
in  I  ounce  of  olive  oil  by  thoroughly  stirring  the  powder  into  the 
oil  with  a  glass  rod.  When  this  has  been  properly  accomplished 
the  oily  emulsion  is  drawn  up  into  a  sterilized  glass  syringe  and  is 
forced  through  the  catheter  into  the  rectum.  Another  ounce  of 
olive  oil  is  then  introduced  in  a  similar  way  through  the  same 
catheter.  The  catheter  is  withdrawn  and  the  patient  is  allowed 
to  remain  upon  the  table  for  one  hour.  If  the  injection  is  given 
at  the  home  it  is  better  to  keep  the  patient  in  bed  for  several 
hours  so  as  to  prevent  any  escape  of  the  salvarsan  emulsion. 

It  will  be  observed  that  arsphenamine  employed  in  this  manner 
is  not  alkalinized  by  sodium  hydroxid  but  is  put  directly  into  the 
olive  oil. 

Some  physicians  employ  salvarsan  for  rectal  injection  by  mak- 
ing an  aqueous  solution,  but  we  prefer  the  oil  on  account  of  its 
blandness  and  because  there  is  less  opportunity  of  irritating  the 


68  THE  TREATMENT  OF  SYPHILIS 

mucous  membrane  of  the  intestine.  This  method  has  been  fol- 
lowed in  giving  weekly  injections  to  patients  and  we  have  had 
no  complaint  of  bowel  irritability. 

When  aqueous  solutions  are  used  sodium  hydroxid  is  employed 
exactly  as  in  making  up  a  solution  for  intravenous  injection. 
The  amount  of  distilled  water  should  be  about  30  cubic  centi- 
meters. 

Patients  remaining  in  the  genupectoral  position  any  length 
of  time  complain  of  great  weariness,  so  that  after  ten  minutes  we 
permit  the  patient  to  assume  the  Sims  position. 

The  physician  must  exercise  care  not  to  permit  any  escape  of 
the  injected  contents. 

We  have  seen  no  occasion  to  utilize  opium  or  any  of  its  deriva- 
tives in  this  form.  Some  operators  have  added  a  little  laudanum 
for  its  soothing  effect,  but  our  experience  has  not  made  this  neces- 
sary. 


CHAPTER  VIII 

THE  TECHNIC   OF   NEOARSPHENAMINE   ADMINISTRATION 

There  are  two  methods  of  introducing  neoarsphenamine  into 
the  system;  one,  the  dilute,  and  the  other,  the  concentrated.  The 
preparation  of  the  patient  for  either  method  is  the  same  as  that 
for  arsphenamine,  and  every  detail  as  set  forth  in  the  preceding 
pages,  as  to  the  physical  condition  of  the  patient,  the  gastro- 
intestinal toilet,  and  the  urinary  examination,  should  be  carried 
out  in  its  entirety. 

The  choice  of  veins  is  the  same. 

Dilute  Intravenous  Administration  of  Neoarsphenamine 

The  apparatus  necessary  for  the  dilute  administration  of 
neosalvarsan  is  practically  identical  with  that  for  salvarsan, 
with  the  exception  that  the  use  of  sodium  hydroxid  is  prohibited. 

The  ampule  of  neosalvarsan  should  be  immersed  in  95  per  cent 
alcohol  for  twenty  minutes  and  all  the  instruments  and  utensils 
should  be  boiled  in  distilled  water.  When  these  latter  are  suffi- 
ciently cool,  the  amount  of  freshly  distilled  and  sterilized  water 
which  is  to  be  utilized  for  the  injection  should  be  run  into  the 
solution  cylinder.  The  quantity  of  water  differs  with  the  amount 
of  neosalvarsan  to  be  utilized.  This  table  will  set  forth  the  proper 
amounts : 

For  Dosage     I  (0.15)  use    25  c.  c. 


"     "     11(0.3) 

'     so  c.  c. 

"     "    111(0.45) 

'     75  c.  c. 

"       IV  (0.6) 

'   100  c.  c. 

"        "         V(o.75) 

'   125  c.  c. 

"        "       VI  (0,9) 

'   150  c.  c. 

This  water  must  be  room  temperature  and  never  hot,  as  hot 
water  is  likely  to  produce  oxidation  and  give  rise  to  reactions. 


70  THE  TREATMENT  OF  SYPHILIS 

The  method  of  opening  the  neosalvarsan  ampule  is  identical 
with  that  of  salvarsan.  The  contents  of  the  ampule  should  be 
scattered  lightly  over  the  surface  of  the  water  and  the  product 
will  then  very  promptly  go  into  solution.  It  is  very  seldom  one 
finds  occasion  to  agitate  this  solution,  even  in  the  slightest  de- 
gree. 

The  neosalvarsan  solution  is  then  filtered  into  the  cylinder 
which  is  to  be  utilized  for  that  purpose,  and  the  freshly  distilled 
and  sterilized  water  as  it  is  used  in,  the  administration  of  salvar- 
san should  be  placed  in  the  other  cylinder. 

The  technic  for  removal  of  the  air  and  for  preparing  for  the 
injection  is  identical  with  that  already  given  for  salvarsan,  and 
practically  every  point  brought  out  in  the  chapter  on  salvarsan 
can  be  duplicated  in  this  connection. 

The  Concentrated  Intravenous  Administration  of  Neoarsphena- 

mine 

One  of  the  reasons  for  the  widespread  popularity  of  neo- 
arsphenamine  is  the  ability  of  the  physician  to  administer  it  in 
concentrated  solution.  The  amount  of  fluid  to  be  used  seems 
to  be  a  matter  of  opinion.  Some  employ  only  lo  c.  c.  of  water  in 
giving  0.9  gram  neosalvarsan  and  others  employ  solutions  up  to 
50  c.  c.    The  favorite  quantity  of  solution  is  about  25  c.  c. 

Two  reasons  are  advanced  for  the  use  of  the  concentrated 
solution.  The  first,  and  doubtless  the  most  general,  is  that  it  is 
"the  lazy  man's  method."  Some  believe  that  as  the  necessary 
preparation  for  the  injection  is  reduced  to  a  minimum,  such  a 
small  amount  can  be  hurriedly  injected. 

The  second  reason  is  that  some  physicians  hesitate  to  intro- 
duce a  large  and  what  they  deem  an  unnecessary  quantity  of 
fluid  into  the  circulation. 

In  the  first  instance  it  is  doubtless  true  that  there  are  prac- 
titioners who  employ  neosalvarsan  on  account  of  its  ease  of 
preparation.  For  some  reason  they  feel  that  the  addition  of 
sodium  hydroxid  to  the  salvarsan  solution  requires  a  degree  of 
skill  or  patience  which  they  do  not  care  to  exercise.  Again,  some 
men  are  inclined  to  the  newer  product  on  account  of  the  small 


TECHNIC  OF  NEOARSPHENAMINE  ADMINISTRATION    71 

amount  of  apparatus  required  for  the  injection.  With  others, 
time  seems  to  be  the  deciding  factor.  They  begrudge  the  few 
extra  minutes  demanded  by  the  use  of  the  gravity  apparatus  and 
consequently  seek  the  quicker  and  more  convenient  way  of 
utilizing  the  services  of  a  Luer  syringe. 

Reasoning  of  this  nature  is  entirely  wrong.  The  matter  of 
time  should  not  enter  into  the  practice  of  medicine,  especially 
when  so  grave  a  disease  as  lues  is  the  enemy  to  be  combatted. 
"The  best  is  none  too  good"  for  the  patient,  and  only  the  best 
method  of  giving  a  remedial  agent  should  be  considered. 

The  relative  value  of  salvarsan  and  neosalvarsan  is  con- 
sidered elsewhere  and  is  not  germane  to  the  subject  now  under 
discussion,  but  we  do  most  emphatically  protest  against  the 
use  of  neosalvarsan  or  any  other  drug  merely  because  it  is  easy 
of  application. 

Time  an  Important  Factor  for  Safety 

K  upon  due  reflection  and  study  of  existing  conditions  the 
physician  determines  upon  the  use  of  neosalvarsan,  he  should 
bear  in  mind  the  strictures  placed  upon  the  rapid  injection  of  the 
drug  by  Dr.  George  W.  McCoy,  U.  S.  P.  H.  S.,  and  discussed  at 
length  in  another  chapter.  He  believes  and  rightfully,  we  feel, 
that  two  minutes  should  be  given  to  the  injection  of  each  deci- 
gram of  arsphenamine  or  twelve  minutes  to  each  maximum  dose 
of  0.6  gram.  As  one  and  one-half  decigrams  of  neoarsphenamine 
are  equivalent  to  one  decigram  of  arsphenamine,  the  natural 
assumption  is  that  Dr.  McCoy  believes  twelve  minutes  should 
be  consumed  in  the  injection  of  0.9  gram  neoarsphenamine. 

If  his  sensible  and  necessary  injunctions  are  carried  out  the 
time  factor  will  not  enter  into  the  consideration  of  the  use  of  con- 
centrated solutions  of  neosalvarsan. 

Of  the  ease  of  preparation,  owing  to  a  lessened  amount  of 
apparatus,  nothing  need  be  said,  for  the  fact  remains  that  the 
method  offers  great  convenience  in  this  particular  connection  and 
we  are  heartily  in  sympathy  with  those  who  employ  it  on  that 
account. 


72  THE  TREATMENT  OF  SYPHILIS 

The  second  reason,  i.  e.,  the  amount  of  water  put  into  the  cir- 
culation, opens  up  a  question  concerning  which  there  has  been 
much  discussion.  Each  school  has  arguments  which  appear 
to  offer  conclusive  proof  that  it  is  correct  in  its  deductions.  We 
must  admit  with  real  frankness  that  long  usage  of  both  methods 
has  not  convinced  us  that  either  is  wrong. 

We  formerly  employed  300  c.  c.  in  administering  0.6  gram 
salvarsan.  No  untoward  effects  were  observed  from  the  use  of  so 
much  fluid.  Later,  the  amount  was  reduced  to  250  c.  c.  and 
finally  to  180,  or  30  c.  c.  per  decigram,  and  we  have  no  present 
expectation  of  going  below  this  amount  in  the  administration  of 
arsphenamine  solutions. 

It  must  be  admitted  that  in  a  few  unguarded  moments,  sal- 
varsan has  been  injected  by  us  for  experimental  purposes,  in  a 
concentration  as  low  as  7  c.  c.  per  decigram.  Grave  fears  followed 
the  use  of  this  low  concentration,  and  the  patients  were  carefully 
observed  for  unpleasant  symptoms,  which,  however,  happily 
did  not  ensue. 

One  swallow  does  not  make  a  summer,  but  the  experience  has 
not  been  repeated  lest  some  of  the  reactions  we  read  about  might 
fall  to  our  lot. 

In  the  use  of  neosalvarsan  we  formerly  used  the  gravity 
method,  giving  every  decigram  of  neosalvarsan  in  20  c.  c.  or 
180  c.  c.  for  a  full  dose.  Added  experience  caused  the  amount  to 
be  lessened  from  time  to  time.  When  the  use  of  a  dilute  solution 
of  neosalvarsan  is  believed  to  be  preferable,  from  100  to  130  c.  c. 
is  deemed  the  proper  amount.  If  it  is  felt  the  patient  can  or 
should  have  a  smaller  amoimt  of  water,  a  concentration  ranging 
from  20  to  50  c.  c.  is  given.  Full  blooded  persons  are  generally 
picked  for  the  greater  concentration.  As  a  rule,  all  things  being 
equal,  25  c.  c.  is  the  average  amount  of  fluid  utilized. 

Danger  of  too  Concentrated  a  Solution 

At  the  instigation  of  a  colleague,  who  enthusiastically  related 
marvelous  serological  results  foUowing  0.9  gram  neosalvarsan  in 
10  c.  c.  of  water,  this  method  was  employed  for  several  injections 


TECHNIC  OF  NEOARSPHENAMINE  ADMINISTRATION    73 

on  four  patients,  all  men  in  good  general  condition.  After  the 
injections  each  man  complained  that  "the  medicine  is  awfully 
strong,"  or  "that  shot  had  too  much  kick  "  or  otherwise  expressed 
his  disapprobation  of  the  method,  not  knowing  of  the  undue 
concentration.  They  experienced  dizziness  and  in  some  instances 
nausea,  and  one  man  felt  an  unpleasant  tingling  of  the  fingers. 
As  these  men  had  received  three  or  more  injections  in  concen- 
trations of  25  c.  c.  or  greater,  it  was  deemed  advisable  to  abandon 
the  use  of  the  more  concentrated  solutions.  It  is  worthy  of  note 
that  the  subsequent  use  of  the  usual  concentration  elicited  no 
complaint  from  these  patients,  nor  did  they  exhibit  further 
dizziness,  nausea,  or  other  symptoms,  during  the  remainder  of 
their  course  of  treatment. 

It  is  hardly  necessary  to  give  an  abundance  of  evidence  as  to 
the  value  of  the  concentrated  method,  on  account  of  its  wide 
usage.  It  may  not  be  amiss,  however,  to  quote  the  experience  of 
Favre  and  Massia  (Press  medicale)  who  successfully  gave  3,150 
injections  in  an  average  of  18  c.  c.  of  water  each.  They  employed 
a  very  fine  needle,  were  able  to  enter  small  veins,  and  found 
that  this  high  concentration  showed  no  evidences  of  vein  irrita- 
tion. Reactions  were  few  and  very  mild  in  character.  They  be- 
lieve that  the  use  of  mercury  with  neosalvarsan  lessens  the  prob- 
abiHty  of  reactions. 

We  urgently  advise  the  use  of  mercury  with  salvarsan  and 
neosalvarsan  in  all  cases  where  tolerated,  not  so  much  for  its 
anti-anaphylactic   as   for   its   anti-luetic   action. 

Technic  of  Concentrated  Method 

In  the  utilization  of  this  method,  the  patient  is  prepared  as  for 
the  dilute  injection  of  either  salvarsan  or  neosalvarsan  and,  in- 
stead of  using  the  apparatus  for  the  dilute  injection,  a  Luer 
syringe  of  from  25  to  50  c.  c.  capacity  takes  the  place  of  the 
double  glass  cylinders,  with  the  bracket,  rubber  tubing  and 
three-way  stopcock.  The  solution  is  made  in  a  wide-mouthed 
glass  graduate  instead  of  in  a  tall,  glass  cylinder. 

After  the  ampule  has  been  sufficiently  immersed  m  alcohol, 
it  is  opened  and  the  contents  sprinkled  on  the  surface  of  the 


74  THE  TREATMENT  OF  SYPHILIS 

freshly  distilled  water  in  the  graduate.  The  amount  of  water 
depends  on  the  ideas  of  the  physician.  Our  practice  is  as  a  rule 
to  give  it  in  about  25  c.  c.  The  neosalvarsan  very  speedily  goes 
into  solution.  As  the  solution  should  be  filtered,  another  glass 
graduate  can  be  utilized  for  this  purpose.  As  soon  as  this  has 
been  completed,  the  solution  is  drawn  into  the  sterilized  Luer 
syringe.  The  needle  is  then  introduced.  When  the  operator  is 
certain  that  the  needle  is  squarely  within  the  vein,  as  indicated 
by  the  backward  spurting  of  the  blood,  the  syringe  is  attached 
to  the  needle  and  the  contents  very  slowly  injected.  The  same 
length  of  time  should  be  consumed  in  administering  the  con- 
centrated solution  as  in  the  dilute.  This  means  that  the  operator 
must  push  the  piston  of  his  syringe  so  slowly  as  to  be  almost 
imperceptible. 

The  amount  of  time  which  Dr.  McCoy  recommends — twelve 
minutes  for  the  full  dose — shows  that  in  giving  a  25  c.c.  con- 
centration not  over  2  c.c.  should  be  injected  a  minute. 

Subcutaneous  Injection  of  Neoarsphenamine 

Neoarsphenamine  can  be  injected  subcutaneously  without 
difficulty  provided  the  operator  has  a  very  careful  technic.  The 
great  desideratum  is  not  to  put  it  into  the  fatty  tissues,  into  the 
fascia  or  into  the  muscles. 

One  of  the  firmest  advocates  of  the  subcutaneous  administra- 
tion of  neosalvarsan  is  Dr.  Joseph  A.  Thomas  of  Valdosta,  Ga. 
He  has  used  this  method  for  six  years,  has  given  a  very  large 
number  of  injections  in  this  manner  and  regards  it  very  highly 
indeed.  The  preparation  of  the  patient  is  looked  upon  as  a  very 
sacred  trust  by  Dr.  Thomas.  He  pays  especial  attention  to  the 
gastro-intestinal  tract  and  insists  that  the  diet  on  the  day  of 
administration  be  exceedingly  simple  and  he  particularly  em- 
phasizes that  no  tomatoes  should  be  ingested,  as  he  has  had 
cases  of  vomiting  where  this  article  of  food  has  been  taken,  but 
he  has  never  seen  vomiting  from  any  other  cause. 

He  is  also  particular  about  testing  the  secretions  of  the  mouth. 
If  he  finds  an  acid  condition  he  utilizes  alkalis  until  the  system 


O 


o 

1 

_c 

T3 

^ 

-a 

o 

'■% 

:3 

^ 

w 

o 

-o 

■z 

o 

^ 

< 

_c 

3 

s 

bC 

<u 

w 

CI 

^ 

K 

'  <u 

■•^ 

en 

X2 

en 

P^ 

ti 

<; 

E/3 

2 

o 

en 

l<^ 

o 

e 

fq 

_d 

^ 

■p 

o 

'o 

OJ 

en 

<u 

<L) 

Iz; 

a 

M 

o 

H 

t3 
3 

O 

B 

-1-1 

-t-> 

I—, 

p 

<U 

:?; 

OJ 

TD 

^3 

hH 

u 

C 

<u 

en 

o 

S 

tD 

CJ 

<L> 

t3 

o 

tS] 

o 

> 

4-1 

^ 

-a 

aj 

4-> 

tn 

H 

iz; 

03 

H 

cd 

1— 1 

T3 

C/1 

W 

> 

.ti 

S 

O 

B 

<u 

^ 

rd 

)-l 

^ 

a 

^ 

<u 

aj 

OJ 

4) 

p 

^ 

-Q 

h-1 

aj 

en 

c^ 

C 

-a 

6 

-u 

p 

3 

s 

"o 

.CT-g 

^ 

"c 

a 

;-< 

> 

CTJ 

P 

1-1 

^ 

O 

^ 

en 

H 

o 

(U 

1-1 

^ 

en 

+J 

TECHNIC  OF  NEOARSPHENAMINE  ADMINISTRATION    75 

becomes  practically  free  from  acidity.  He  believes  this  to  be 
essential  for  the  prevention  of  unpleasant  after-effects,  although 
in  a  letter  to  the  author  he  says  that  he  has  not  yet  had  any 
reactions. 

Dr.  Thomas  then  examines  the  patient  carefully  for  indications 
as  to  renal,  cardiac  or  neurological  disturbances.  Those  caused  by 
syphilis  do  not  form  contraindications  to  the  drug  but,  if  present 
from  other  causes,  he  treats  the  cause  before  going  further  with 
neosalvarsan  administration. 


Dr.  Thomas'  Technic 

For  the  employment  of  neosalvarsan  subcutaneously,  Dr. 
Thomas  utilizes  (i)  a  10  c.  c.  Luer  syringe  mth  a  20  gauge 
platinum  needle;  (2)  a  syringe  with  a  small  needle  for  the  local 
anesthetic;  (3)  a  glass  graduate  which  will  hold  20  c.  c;  and 
(4)  freshly  distilled,  sterilized  water. 

After  the  ampule  of  neosalvarsan  has  been  thoroughly  sterilized 
by  immersion  in  alcohol,  he  opens  it  and  dissolves  the  contents 
of  the  ampule  in  10  c.  c.  of  freshly  distilled  water  at  room  tempera- 
ture. 

The  patient  is  placed  upon  his  abdomen  and  the  skin  at  the 
angle  of  the  scapula  is  painted  with  iodin  around  the  point  an 
inch  or  two  in  circumference.  It  is  then  anesthetized  with  a 
few  drops  of  cocain.  The  neosalvarsan  solution  is  drawn  up 
into  the  Luer  syringe  and  is  injected  UNDER  the  skin  and  not 
in  it  or  in  the  fascia  but  in  the  connective  tissue  between  the 
skin  and  the  fascia.  Dr.  Thomas  lays  particular  stress  upon  the 
importance  of  this  point. 

The  injection  should  be  given  very  slowly.  He  advises  that  the 
operator  make  certain  the  needle  is  free  and  not  in  the  skin  by 
gently  moving  the  needle  from  side  to  side.  Upon  the  completion 
of  the  injection  the  site  should  be  massaged  thoroughly,  so  that 
there  may  be  a  wide-spread  distribution  of  the  solution  under 
the  skin.  This  massage  prevents  the  formation  of  a  lump.  The 
point  of  entrance  of  the  needle  is  covered  with  sterile  gauze  and 
adhesive. 


76  THE  TREATMENT  OF  SYPHILIS 

Dr.  Thomas  says  that  very  little  pain  follows  this  method  of 
administration  and  v/hen  it  is  observed  the  pain  will  practically 
always  be  found  to  be  intercostal  and  largely  referred  to  the 
anterior  aspect  of  the  chest.  The  patients  feel  as  if  they  had  a 
pain  over  the  heart,  but  the  pain  in  Dr.  Thomas'  opinion,  is  of 
small  consequence  and  it  has  been  very  seldom  necessary  for 
him  to  administer  an  opiate. 

The  advantage  of  the  subcutaneous  administration  of  neosal- 
varsan  over  other  methods  is  that  it  is  unusually  simple,  is  with- 
out danger,  gives  at  least  as  good  results  as  the  others,  and  there 
is  practically  no  after-pain  and  no  detention  from  business. 
Dr.  Thomas  believes  that  the  action  of  the  drug  is  prolonged  for 
about  two  weeks.  He  has  injected  several  hundred  patients  in 
this  manner  and  has  never  had  any  serious  after-effects  and 
only  one  of  his  patients  has  been  compelled  to  go  to  bed.  In 
this  instance  the  temperature  went  to  105°  F.  This  patient  was 
in  his  secondaries  with  a  malignant  infection  and  the  medical 
attendant  feels  that  the  cause  of  the  rise  in  temperature  was  due 
to  the  liberation  of  many  endotoxins  following  the  administra- 
tion of  the  spirochetecide. 


< 
o 


en      H 


=2  V 

ci     O 
O 


M 


^    .S    c 


.2    o 


1=1  -a 


CHAPTER  IX 

THE    METHODS    OF    EMPLOYING    THE    MERCURIALS    AND    IODIDES 

The  Intramuscular  Method  of  Injecting  Mercury 

The  intramuscular  injection  of  the  soluble  or  insoluble  forms 
of  mercury  requires  considerable  care  and  should  not  be  re- 
garded lightly. 

The  favorite  site  for  injection  is  about  one  inch  from  the 
crease  of  each  buttock  and  the  parts  must  be  sterilized,  prefera- 
bly with  tincture  of  iodin. 

Platinum  needles  of  20  gauge  are  best  adapted  for  this  work, 
especially  when  soluble  preparations  are  being  used.  The 
needles  should  be  two  inches  long,  so  that  the  mercury  can  be 
deposited  in  the  muscle  and  not  in  the  fat  or  subcutaneous  tissue. 
Careful  examination  of  the  needle  should  be  made  before  each 
injection  to  ascertain  any  structural  weakness.  If  a  needle  is 
broken  off  in  the  gluteal  region  the  parts  must  immediately  be 
laid  wide  open  and  the  part  extracted,  for  needles  in  that  section 
of  the  body  are  rapid  travelers. 

The  needle  must  be  thoroughly  sterilized  before  use  and  after 
the  injection  the  bore  must  be  cleared  of  the  detritus,  lest  some 
may  be  left  in  the  bore  and,  having  partially  decomposed,  be 
injected  into  the  body  at  the  time  it  is  next  employed. 

When  any  form  of  mercury  is  to  be  injected,  we  strongly 
recommend  an  all  glass,  2  c.  c.  Luer  syringe. 

In  carrying  out  the  operation  of  injection,  after  the  site  has 
been  sterilized,  we  plunge  the  needle,  minus  the  syringe,  deeply 
into  the  muscle,  with  one  short  stab.  This  method  causes  the 
patient  much  less  pain  than  slow  penetration. 

If  blood  comes  out  of  the  shank  of  the  needle,  it  should  imme- 
diately be  withdrawn,  as  a  vessel  has  been  entered.  We  have 
seen  patients  collapse  after  an  injection  of  mercury  when  the 


78  THE  TREATMENT  OF  SYPHILIS 

syringe  was  attached  to  the  needle  and  no  precaution  against  the 
entrance  of  a  blood  vessel  observed. 

If  blood  does  not  follow  the  introduction  of  the  needle,  the 
syringe  should  be  attached  and  the  contents  of  the  barrel  slowly 
injected. 

We  heartily  condemn  imdue  haste  in  making  these  injections 
as  we  believe  much  of  the  soreness  following  this  form  of  medica- 
tion is  due  to  too  rapid  introduction. 

After  the  mercury  has  been  deposited  in  the  muscle,  the  needle 
is  withdrawn  and  the  part  slowly  and  thoroughly  massaged  under 
a  piece  of  gauze.  This  acts  to  prevent  the  lumps  which  appear 
following  gluteal  injections,  forming  the  so-called  "cobble- 
stone"  buttocks. 

As  soon  as  bleeding  stops,  the  point  of  entrance  is  sealed  with 
collodion  to  prevent  possible  infection. 

The  Inunction  Method 

Many  physicians  beUeve  the  inunction  method  is  the  best, 
especially  if  the  rubbing  can  be  done  by  a  person  experienced  in 
such  work.  This  method  has  the  advantages  of  causing  no  pain, 
of  promptly  and  thoroughly  saturating  the  body  with  the  drug, 
and  of  non-interference  with  the  digestive  tract.  Inunction  is 
quite  necessary  in  persons  who  are  old  or  debilitated,  or  very  fat, 
and  in  pregnant  women,  as  these  types  cannot  stand  injections. 

The  inimction  has  an  added  advantage  in  that  it  is  stored  up 
in  the  follicles  of  the  skin  and  is  eliminated  through  the  urine 
long  after  the  rubbings  have  been  discontinued. 

The  old-fashioned  unguentum  hydrargyrum  is  often  used,  but 
we  prefer  an  ointment  made  as  herein  set  forth,  as  it  leaves  no 
trace  on  the  skin  and  is  not  unpleasant  in  odor: 

loo  parts  of  mercury  are  mixed  with  15  parts  of  anhydrous 
lanolin  and  3  parts  of  olive  oil.  Carefully  stir,  adding  the  mer- 
cury in  small  quantities,  but  only  when  no  more  mercury  pellets 
are  visible.  Then  add  a  nearly  cold  mixture  of  112  parts  of  lard 
and  70  parts  of  mutton  tallow,  this  latter  mixture  having  been 
prepared  by  melting  together,  and  mix  the  whole  carefully.    The 


THE  MERCURIALS  AND  IODIDES  79 

resultant  salve  is  of  bluish-gray  color  and  no  mercury  pellets 
should  be  visible  to  the  naked  eye. 

Anatomical  Sites  for  Inunctions 

We  suggest,  if  possible,  inunctions  just  before  retiring  on  seven 
successive  days  on  these  anatomical  locations: 

ist  day — Right  and  left  calves. 

2nd"    Right  thigh. 

3rd  "    Left  thigh. 

4th  "    Abdomen. 

5th  "    Chest. 

6th  "    Right  arm  and  forearm. 

7th  "    Left  arm  and  forearm. 

The  rubbing  should  be  continued  for  twenty  minutes  or  until 
all  the  mercury  has  disappeared. 

After  the  inunction  on  the  seventh  day,  the  patient  should 
take  a  hot,  soapy  bath  and  the  following  day  commence  another 
seven  day  series. 

The  patient  should  wear  woolen  undergarments  and  change 
them  only  after  the  seventh  day  bath. 

The  inunctions  are  continued  as  long  as  the  case  demands  and 
each  case  must  be  individualized. 

Administration  by  the  Mouth 

We  mention  this  method  only  to  condemn  it  and  believe  the 
physicians  who  pursue  this  line  of  treatment  are  following  an 
ignis  fatuus. 

Many  a  case  of  tabes  and  paresis  has  followed  the  use  of  mer- 
cury per  OS,  the  patients  meantime  being  sublimely  unconscious 
of  their  ultimate  fate. 

Continued  use  of  mercury  by  this  means  impairs  the  power  of 
the  alimentary  tract  to  absorb  it  and  anemia,  diarrhea  and  gen- 
eral debility  often  follow  its  continued  use. 

Fumigation  and  Inhalation 

These  methods  are  recommended  when  there  are  extensive 
ulcerating  lesions,  involving  the  deeper  structures  but  are  not 


8o  THE  TREATMENT  OF  SYPHILIS 

suggested  for  ordinary  cases.     When  indicated,  however,  these 
means  are  of  real  value. 

Intravenous  Method 

This  is  not  yet  sufficiently  perfected  to  permit  of  discussion  of 
a  helpful  nature.  We  doubt  not  that  eventually  the  intravenous 
route  will  form  one  of  the  standard  methods. 

Form  of  Mercury  to  be  Used 

The  question  arises  as  to  whether  one  wiU  use  a  soluble  or  in- 
soluble form  of  mercury.  The  insoluble  in  the  form  of  the  salicy- 
late is  very  popular,  although,  both  calomel  and  gray  oil  have 
their  ardent  advocates.  For  example,  Dr.  J.  A.  Fordyce,  if  he  em- 
ploys an  insoluble  form,  utilizes  gray  oil  *'in  the  form  of  mercurial 
cream,  of  which  5  minims  represent  i  grain,  in  a  series  of  ten  or 
twelve  injections,  or  salicylate  of  mercury  40  per  cent  suspension 
in  doses  of  i  to  3  grains,  gradually  increased,  ten  to  twelve  in- 
jections constituting  a  course." 

We  have  utilized  this  form  of  treatment  with  results  not  en- 
tirely satisfactory.  Our  dissatisfaction  was  largely  due  to  the 
soreness  which  was  likely  to  foUow  the  injections  and  particularly 
to  the  formation  of  lumps  in  the  buttocks,  the  "cobble-stone" 
buttocks,  in  which  condition  mercury  was  found  to  be  unab- 
sorbed,  sometimes  weeks  after  the  original  injection. 

We  thereupon  experimented  with  the  succinimid,  which  is  a 
soluble  product.  This  was  found  to  work  well  in  clinics  where  the 
patients  were  men  used  to  very  heavy  work  and  who  were  not 
easily  affected  or  disturbed  by  localized  soreness,  but  in  private 
practice  it  proved  to  be  altogether  too  painful,  nor  did  the  benzo- 
ate  work  to  our  satisfaction. 

The  soluble  mercury  of  choice  we  have  found  to  be  the  bi- 
chlorid,  which  we  ordinarily  administer  in  the  beginning  of 
treatment  in  3^  grain  doses.  If  that  is  readily  taken,  the  dose 
is  increased  to  3^  grain  and  then  to  i  grain. 

Dr.  Fordyce  {Amer.  Jour.  Med.  Sci.,  October,  1916)  advised 
giving  a  soluble  mercury  intramuscularly  every  other  day  and 
quoted  the  bichlorid   as  his  preference  of  the  soluble  forms, 


Iz: 

o 

H 

CJ 

w 

1— > 

;z; 

t— ( 

I-) 

< 

"S 

a 

t3 

en 

q 

;-l 

« 

o 

3 

« 

.s 

^ 

1— 1 

F^ 

t) 

a 

o 

cfi 

o 

t3 

T3 

OJ 

OJ 

Q. 

u 

>% 

H 

;3 

^ 

;-< 

HH 

Ul 

^ 

o 

« 

'S) 

O 

CJ 

P^ 

cJ 

bio 

(J 

M 

C 

1-1 

^ 

CI 

P 

en 

b 

2; 

_fl 

^ 

1 

<N 

O 

< 

<U 

<u 

Xi 

-C 

g 

2 

g 

3 

"o 

O 

en 

P4 

^ 

>* 

U3 

<U 

CA) 

^ 

bO 

^ 

C! 
•t-i 

<U 

ii 

(U 

>. 

a 

en 

(U 

a> 

-a 

-C 

H 

H 

THE  MERCURIALS  AND  IODIDES  8l 

giving  from  twenty  to  thirty  injections  either  daily  or  every  other 
day. 

A  Convenient  Means  of  Mercurial  Administration 

One  objection  to  the  hypodermic  use  of  mercury  has  hereto- 
fore been  the  frequent  inability  to  obtain  an  absolutely  certain 
dosage  of  mercury,  especially  where  it  has  been  put  up  in  an  oily 
suspension  by  the  local  pharmacist.  Several  years  ago  there 
came  to  our  attention  an  ingenious  method  of  holding  insoluble 
or  soluble  mercurials  in  the  form  of  coUapsule  hypo-fills,  which 
consist  of  bulbs  made  of  gelatin  holding  an  exact  amount  of 
the  mercurials.  By  means  of  these  coUapsules  we  carried  on  a 
long  series  of  experiments  utilizing  the  saUcylate,  calomel,  suc- 
cinimid,  benzoate  and  bichlorid.  The  mercurial  is  held  in  a  base 
containing  neutral  vegetable  anhydrous  fats  and  when  intro- 
duced into  the  body  breaks  down  in  the  form  of  alkaline  pal- 
mitates  and  glycerin.  The  bichlorid  is  readily  absorbed,  the 
injection  is  followed  by  practically  no  pain  and  the  "cobble- 
stone" buttock  is  something  unknown. 

The  great  advantage  of  the  use  of  collapsules  is  that  the  physi- 
cian is  certain  of  exact  dosage  and  he  is  also  given  a  most  con- 
venient method  of  administration.  Our  experience  has  been  that 
the  use  of  mercury  in  this  form  seems  to  increase  the  body  weight 
and  the  arsphenamine  is  very  materially  aided. 

From  the  cut  given  herewith  it  will  be  observed  that  the  gelatin 
top  of  the  coUapsule  is  clipped  off,  and  the  contents  squeezed 
into  a  2  c.  c.  Luer  syringe,  which  is  warm  from  the  previous 
sterilization,  and  it  is,  therefore,  melted  sufficiently  to  permit 
of  immediate  injection  into  the  body. 

Advantages  and  Disadvantages  of  Soluble  Mercury 

The  great  advantage  of  mercury  in  the  treatment  of  S3^hilis 
is  to  have  it  as  constantly  in  the  system  as  possible. 

It  might  seem  almost  suicidal  to  advocate  the  use  of  bicholorid 
of  mercury  in  from  3^  to  i  grain  doses.  This,  however,  is  the 
dosage  which  Fordyce  has  employed  in  his  clinics  for  a  long  time 
without  any  difficulty,  and  we  have  also  utilized  it  to  the  very 


82  THE  TREATMENT  OF  SYPHILIS 

best  advantage.  It  means,  however,  that  the  patient  should  come 
every  other  day  for  treatment  and,  while  this  can  be  accom- 
plished so  far  as  the  ordinary  dispensary  patient  is  concerned,  it 
is  often  difficult  for  the  private  patient  unless  he  be  in  a  hospital. 

Another  disadvantage  of  bichlorid  is  the  possibility  of  a  renal 
nephritis.  We  have  never  seen  such  a  condition  but  the  possibil- 
ity is  ever  present  and  must  be  most  carefully  considered. 

The  use  of  bichlorid  means  that  the  urine  must  be  constantly 
examined  so  that  the  condition  of  the  kidneys  can  be  at  all  times 
known  to  the  physician. 

If  the  patient  can  come  to  the  office  every  other  day,  or  even 
twice  a  week,  we  recommend  the  bichlorid;  if  it  is  impossible 
and  the  patient  can  only  be  seen  once  a  week,  the  salicylate  is 
preferable.  In  some  cases  one  grain  of  bichlorid  injected  once 
a  week  has  been  absorbed  so  slowly  that  we  have  been  content 
to  give  weekly  injections  of  one  grain  each. 

Iodides 

The  employment  of  the  iodides  in  the  treatment  of  syphilis 
has  undergone  a  very  radical  change  since  the  introduction  of 
salvarsan  as  an  anti-luetic  agent.  It  was  formerly  a  part  of  the 
stock  treatment  of  the  syphilitic  and  after  vigorous  mercurial 
medication  he  was  placed  upon  the  iodides,  preferably  the  iodid 
of  potassium.  Despite  the  fact  that  this  drug  disarranges  the 
stomach  of  many  patients,  it  was  very  generally  utilized,  al- 
though at  times  other  preparations  of  iodin,  such  as  salts  of 
sodium,  strontium,  and  ammonium,  have  been  used.  There 
are  on  the  market  a  number  of  proprietary  products  containing 
iodides,  which  have  been  formulated  in  combinations,  tending 
to  eliminate  the  uncomfortable  and  unpleasant  features  caused 
by  taking  the  raw  iodides. 

Spirochetae  not  Affected  by  Iodin 

We  have  learned,  however,  that  iodin  has  little  or  no  effect 
upon  the  spirochetae.  This  was  first  brought  to  the  attention 
of  the  profession  by  Colonel  (then  Captain)  H.  J.  Nichols,  U.  S. 
Army  {Journal  of  Experimental  Medicine,  p.  196,  191 1). 


2        c 
^       .2 


12;    -a        5 

I— I      -r-  t5 


^  >» 


hH        S 


O 


o  *J 


>% 


5    o 


c 

<N 

8 

d 

OJ 

0 

-r^ 

Ml 

-a 

-(-' 

0 

o 

^ 

0 

n 

.0 

-a 

=5 
0 

in 

0 

O   fi  :S 


d    o    o 


THE  MERCURIALS  AND  IODIDES  83 

Clinical  observation  has  demonstrated  that  the  drug  does  not 
change  the  Wassermann  reaction  and  it  has  practically  no  effect 
upon  primary  syphilitic  lesions.  The  facts  would  seem  to  con- 
demn iodin  as  a  drug  for  use  in  syphilis;  however,  it  has  a  very 
definite  place  in  the  treatment  of  tertiary  syphilis  as  well  as  in 
syphilis  of  the  nervous  system.  The  particular  effect  of  the  drug 
seems  to  show  itself  upon  the  gummata.  Just  how  it  works  to 
produce  this  effect  upon  gummata  is  a  discussed  question,  but 
the  fact  remains  that  in  the  conditions  mentioned  it  is  of  value. 

lodid  of  potassium  can  be  used  by  the  mouth  or  by  hypoder- 
mic injection  and  some  syphilologists  have  utilized  it  by  in- 
travenous injection  and  also  by  enema.  The  most  common 
method  of  oral  administration  is  that  of  the  saturated  solution; 
100  grains  of  the  potassium  iodid  are  dissolved  in  sufficient  water 
to  make  100  drops.  Each  drop,  therefore,  contains  i  grain.  It 
is  usual  to  start  the  patient  off  with  10  drops  one  hour  after 
each  meal  in  a  half  glass  of  milk  or  water  and  to  increase  one 
drop  at  each  dose  or  three  drops  a  day  until  the  patient  shows 
signs  of  intolerance.  By  giving  the  drug  an  hour  after  each  meal 
the  potassium  iodid  finds  a  more  ready  reception  in  the  stomach, 
because  the  starchy  contents  have  been  changed  into  sugar. 

Another  method  of  administration  is  the  formula  of  Ricord. 
He  did  more  to  popularize  the  drug  in  the  treatment  of  syphilis 
than  any  other  man.    This  formula  is: 

Kali  iodidi  4 .  o 

Syrupi  corticis  aurantii         250.0 

M.  Sig.  One  tablespoonful  three  times  a  day. 

If  the  drug  is  to  be  administered  hypodermatically,  from  4  to  8 
grains  are  given  in  50  c.  c.  solution  and  any  pain  which  may  ac- 
company the  injection  can  be  corrected  by  the  introduction  of 
codein  to  the  solution. 

We  cannot  speak  of  the  intravenous  use  of  potassium  iodid 
as  we  have  had  no  experience  therewith. 

If  the  enema  form  of  administration  is  used,  the  large  bowel 
should  be  thoroughly  cleansed  with  an  ordinary  enema;  then  it  is 


84  THE  TREATMENT  OF  SYPHILIS 

well  to  inject  from  i  to  3  drams  of  potassium  iodid  in  pepton- 
ized milk  to  which  have  been  added  5  drops  of  laudanum. 

Only  Heavy  Doses  of  Iodides  are  Effective 

The  great  value  of  the  iodides  is  observed  in  heavy  doses. 
Many  physicians  are  in  the  habit  of  prescribing  10  grains  three 
times  a  day.  There  is  no  more  advantage  of  putting  this  amount 
of  iodid  into  the  patient's  stomach  than  into  his  shoe.  If  results 
are  to  be  obtained,  the  drug  must  be  administered  in  heroic 
doses.  We  have  seen  many  cases  in  which  from  100  to  125 
grains  were  administered  three  times  daUy.  In  these  cases,  par- 
ticularly those  in  which  gummata  were  present,  the  results  were 
a  little  short  of  marvelous,  as  the  lesions  would  actually  seem 
to  fade  away  under  this  heavy  dosage. 

One  of  the  difficulties  in  taking  the  drug  are  the  coryzal  symp- 
toms which  follow  the  administration  of  comparatively  small 
amounts.  This  is  due  to  the  fact  that  the  average  dose  seems  to 
be  excreted  by  means  of  the  nasal  mucous  membrane.  The  large 
dosage  is  eliminated  by  the  kidneys  and  causes  little  or  no  nasal 
complications. 

Potassium  iodid  in  large  doses  is  something  of  a  heart  de- 
pressant and  it  is  urged  that  when  patients  are  given  these  large 
amoimts  they  be  not  permitted  to  carry  on  heavy  physical  work; 
they  should  be  watched  with  considerable  care. 

The  amount  of  potassium  iodid  which  the  patient  can  absorb 
varies  with  the  individual;  some  show  signs  of  iodism  after  a  very 
small  amount  of  the  drug.  As  about  80  per  cent,  is  excreted 
daily  there  is  an  accumulation  in  the  body  from  the  daily  dosage. 
Therefore,  a  heavy  dose  should  be  employed  until  the  patient 
has  reached  his  limit  when  the  dose  should  be  moderated. 

Iodism 

Iodism  is  first  brought  to  the  patient's  attention  by  a  metallic 
taste  in  the  mouth  or  by  a  coryza,  with  sneezing  and  the  other 
symptoms  of  a  head  cold.  In  some  instances  this  coryza  becomes 
somewhat  severe,  but  it  passes  away  by  a  diminution  or  a  com- 
plete cessation  of  the  drug  for  the  time  being. 


Cl 

> 

x 

(V( 

& 

G 

u 

(N 

M 

S 

XI 

P^ 

c 

o 

o 

:z: 

n 

^ 

H 

O 

o 

w 

X 

a; 

1— > 

o 

^ 

o 

(J 

c3 

3 

PS 

J3 

H 

< 

t) 

^ 

tj 

-r; 

+-1 
3 

r/j 

_N 

bC 

^ 

OJ 

6 

1— 1 

"o 

f5 

-C 

(73 

OJ 

X 

-o 

fTi 

<u 

aj 

,^ 

03 

o 

J=l 

c 

THE  MERCURIALS  AND  IODIDES  85 

The  use  of  potassium  iodid  is  very  often  attended  with  gastro- 
intestinal disturbances  as  well  as  dermatological  lesions,  such 
as  iodid  pimples,  which  are  closely  analogous  to  acne  vulgaris. 

The  physician  should  do  everything  in  his  power  to  prevent 
over-stepping  the  bounds  of  tolerance  in  the  administration  of 
this  drug.  It  is  well  to  have  daily  examinations  of  the  urine 
made  to  observe  the  excretion  of  iodin.  Dr.  Loyd  Thompson 
{Syphilis,  p.  251,  1916)  recommends  mixing  2  c.  c.  each  of  urine 
and  pure  hydrochloric  acid  and  adding  a  few  drops  of  chloro- 
form. The  presence  of  iodin  is  indicated  by  a  pink  coloration  of 
the  chloroform  upon  settling  to  the  bottom  of  the  tube,  following 
its  inversion  two  or  three  times.  In  the  event  that  iodin  is  not 
discovered,  the  physician  would  do  well  to  watch  the  case  slowly 
lest  iodism  appear. 

Resume  of  the  Treatment  of  Sjrphilis 

Examination  of  Patient. — Patient  to  be  examined  very  care- 
fully to  see  if  any  contraindications  to  arsenical  treatment  be 
present. 

Urine  to  be  examined  before  the  injection. 

No  food  in  the  stomach  for  six  hours  before  injection  or  four 
hours  thereafter,  and  patient  to  rest  in  bed  after  the  injection. 

Dosage  of  Arsphenamine  or  Neoarsphenamine 

Drug  dissolved  in  room-temperature,  freshly  distilled,  steril- 
ized water  and  injected  very  slowly. 

Initial  dose  for  men  0.2  or  0.3  gram  salvarsan  or  0.3  or  0.45 
gram  neosalvarsan;  for  women,  0.2  gram  salvarsan  or  0.3  gram 
neosalvarsan. 

Subsequent  doses  for  men  0.4  to  0.6  gram  salvarsan  or  0.6 
to  0.9  gram  neosalvarsan;  for  women,  0.4  or  0.5  gram  salvarsan 
or  0.6  to  0.75  gram  neosalvarsan. 

Mercury 

Soluble — bichlorid:  from  3<C  to  3^  grain  injected  in  the  buttock 
three  times  a  week,  if  possible. 


86  THE  TREATMENT  OF  SYPHILIS 

Insoluble — salicylate:  i  grain  injected  into  the  buttock  once 
a  week. 

Urine  should  be  examined  at  frequent  intervals  to  ascertain 
the  presence  of  any  renal  irritation  caused  by  the  mercury. 

Iodides 

Begin  with  lo  drops  saturated  solution  three  times  a  day  in 
water  or  milk,  increase  so  that  the  patient  is  taking  from  lOO 
to  125  grains  three  times  a  day  when  the  occasion  requires. 

Courses  of  Treatment 

Salvarsan  or  neosalvarsan  to  be  given  at  from  5  to  7  day  in- 
tervals untU  eight  injections  have  been  administered.  Mercury 
to  be  administered  for  twelve  weeks;  three  times  a  week  in  the 
soluble  form,  if  possible,  and  once  a  week  in  the  insoluble  form. 

Iodides  to  be  administered  when  syphiHtic  gummata  are 
present,  in  latent  syphilis,  and  in  syphilis  in  which  the  nervous 
system  is  involved. 

After  one  course  the  patient  to  rest  for  four  weeks  and  then  a 
Wassermann  taken. 

If  positive,  a  second  course  is  necessary  and  subsequent  courses 
depend  upon  the  condition  of  the  Wassermann. 

If  negative,  a  Wassermann  to  be  taken  at  monthly  intervals 
for  a  year,  after  which  they  should  be  taken  at  least  quarterly 
over  a  long  period. 

Before  pronouncing  a  patient  cured,  there  should  also  be  a  per- 
sistent negative  Wassermarm  of  the  spinal  fluid. 

General  Treatment 

It  must  be  remembered  that  syphilis  is  a  constitutional 
disease  and  the  patient  is  very  likely  to  require  other  than  anti- 
luetic  treatment.  On  account  of  the  destruction  of  the  red  blood 
corpuscles  by  the  inroads  of  the  disease,  tonics  are  usually  de- 
manded. For  emaciation,  cod  Hver  oil  is  recommended;  for 
anemia,  iron;  and,  for  the  stimulation  of  general  nutrition  as 
well  as  the  nervous  system,  strychnin  is  advised.    Tincture  of 


:S    8 


^    fi 


o  ^ 

a,  T3 


■       I"? 

s 

4:j    o 


THE  MERCURIALS  AND  IODIDES  87 

nux  vomica  is  also  a  tonic  which  works  to  advantage  in  syphilis, 
particularly  when  combined  with  tincture  of  cardamom  comp. 
and  glycerin. 

The  patient's  weight  should  be  observed  from  time  to  time  and 
the  condition  of  the  blood  should  also  be  watched  by  means  of 
the  hemoglobinometer. 

Many  patients  do  well  under  a  Turkish  bath,  without  the  cold 
plunge,  once  or  twice  a  week.  This  aids  in  elimination  and  is  of 
particular  assistance  in  those  cases  in  which  the  mercury  may  be 
slow  in  leaving  the  system. 

Hydrotherapeutic  Treatment 

In  addition  to  the  hygienic  treatment  of  the  syphilitic  as  laid 
down  in  another  chapter,  the  hydrotherapeutic  form  of  treat- 
ment should  not  be  overlooked  when  patients  can  afford  such. 
The  various  hot  springs  of  the  country  offer  specific  methods  of 
hydrotherapy  which  are  undoubtedly  beneficial.  Patients  who 
are  not  able  to  go  to  hot  springs  for  treatment  of  this  nature  are 
often  benefited  by  the  baths  at  such  resorts  as  Saratoga  Springs. 
There  is  nothing  at  Saratoga  which  can  be  claimed  to  possess 
curative  properties,  but  patients  who  are  sent  there  are  given 
the  eliminating  treatment  with  carbonated  baths  at  the  Lincoln 
Bath  House  at  temperatures  var3dng  from  97°  to  110°.  In 
alternation  with  these  baths,  the  electric  cabinet  baths  with  a 
fan  spray  following,  for  reaction,  are  employed.  Very  satisfac- 
tory results  have  been  observed  when  this  fine  of  treatment  has 
been  carried  out  in  conjunction  with  the  usual  anti-luetic  treat- 
ment. 


CHAPTER  X 

EJEACTIONS     AND    ACCIDENTS     FOLLOWING    THE     USE     OF 
ARSPHENAMINE 

Reactions 

Sometimes  during  an  injection  of  arsphenamine  or  neoar- 
sphenamine  certain  phenomena  will  be  noted  which  have  been 
termed  nitroid  crises.  These  include  nausea,  malaise,  flushing 
of  the  face,  headache,  precordial  distress  and  dyspnea,  and  are 
usually  inconsequential.  Being  of  an  anaphylactoid  type,  they 
can  be  relieved  by  the  intramuscular  injection  of  from  ten  to 
twenty  minims  of  a  i:iooo  solution  of  epinephrin.  When  pa- 
tients are  known  to  exhibit  such  symptoms,  difficulty  can  be 
obviated  by  the  injection  of  the  epinephrin  ten  minutes  before 
the  anticipated  injection  of  salvarsan. 

Dr.  J.  H.  Stokes  of  Rochester,  Minn.  (/.  A.  M.  A.,  Jan.  25, 
1919)  observed  that  the  epinephrin  administers  a  shock  to  the 
system  by  its  powerful  vasomotor  action  and  states  that  he  has 
"seen  occasions  in  which  patients  have  for  the  moment  seemed 
in  as  much  risk  of  serious  damage  from  the  therapy  as  from  the 
original  arsphenamine  reaction." 

Dr.  Stokes  thereupon  set  out  to  discover  a  method  which 
should  protect  his  patients  against  reactions  following  the  use  of 
arsphenamine  and  to  support  his  view  that  such  a  reaction  is  a 
manifestation  of  anaphylactic  shock.  He  sought,  in  other  words, 
an  anti-anaphylactic  agent.  For  this  purpose  he  utilized  atropin, 
which  has  an  inhibitory  effect. 

It  was  first  employed  in  the  case  of  a  woman  whose  intolerance 
to  neoarsphenamine  was  beyond  doubt.  Suffering  from  a  florid 
follicular  secondary  syphilid,  the  initial  moderate  dose  was 
followed  by  a  rather  sharp  Jarisch-Herxheimer  reaction,  and, 
during  her  first  course  of  five  injections,  she  gave  abundant 
evidence  of  gradually  increasing  intolerance  to  the  drug. 


REACTIONS  FOLLOWING  USE  OF  ARSPHENAMINE       89 

Six  weeks  later  the  administration  of  0.3  neoarsphenamine 
was  followed  in  two  minutes  by  an  intense  scarlet  flush  and 
edema  of  the  face  and  neck,  with  cough,  stridor  and  vomiting. 
A  subcutaneous  injection  10  minims  of  i  :iooo  of  epinephrin  re- 
stored her  completely. 

A  week  later  the  woman  was  given  1/50  grain  of  atropin 
h}'podermatically  and  fifteen  minutes  later  received  0.6  neo- 
arsphenamine, with  only  a  sHght  reaction,  and  at  the  period  of 
the  third  injection  the  following  week  the  use  of  atropin  per- 
mitted the  injection  of  0.7  gram  with  only  distinct  nausea  as  a 
disagreeable  factor. 

Successful  Employment  of  Atropin 

At  a  later  period,  deciding  to  produce,  if  possible,  antianaphy- 
laxis  by  atropin,  Dr.  Stokes  gave  the  woman  intravenously 
0.05  gm.  of  the  drug  in  0.5  c.  c.  of  water.    He  goes  on  to  say: 

"The  neoarsphenamine  used  was  of  the  same  control  number 
as  that  employed  for  the  previous  injection,  which  had  shown 
itself  capable  of  producing  marked  reaction  in  this  patient 
(Control  V  U  J).  Following  the  injection  of  the  half  decigram 
dose,  the  patient  became  slightly  dizzy  and  was  a  trifle  nauseated 
on  returning  to  bed.  One  hour  after  the  preliminary  injection 
the  patient  received  0.55  gm.  of  neoarsphenamine  intravenously 
in  concentrated  solution,  injected  at  the  usual  rate.  The  com- 
plete inhibition  of  all  reaction  was  striking.  There  was  no  flush, 
no  nausea  nor  vomiting,  no  dizziness,  cough  nor  stridor.  The 
eyes  became  slightly  suffused.  The  patient  felt  so  much  better 
than  usual  as  to  astonish  her  and  all  those  who  knew  of  her  re- 
actions. She  was  returned  to  her  room,  and  no  reaction  was  re- 
ported for  twenty-four  hours.  At  the  end  of  this  time,  without 
rise  of  temperature  or  any  other  marked  systemic  symptoms,  a 
generalized  macular  erythma  of  the  typical  late  toxic  type 
appeared.  It  was  not  accompanied  by  constitutional  symptoms 
and  disappeared  two  or  three  days  later.  It  was  judged  wise, 
however,  not  to  invite  an  exfoliative  dermatitis  by  any  further 
arsenotherapy." 


90  THE  TREATMENT  OF  SYPHILIS 

Dr.  Stokes  comments  further  on  the  matter: 

"This  case  was  surrounded  by  all  the  precautions  against 
pseudoreaction  that  we  could  devise.  The  reactions  observed 
were  t3^ical  of  the  acute  nitritoid  crisis  and  we  felt  that  the 
sequence  of  events,  as  described,  had  not  been  modified  by 
presuppositions  on  the  part  of  the  patient  or  by  hysterical  man- 
ifestations. Abundant  objective  evidence  of  the  patient's  in- 
tolerance was  available.  Not  the  least  interesting  suggestion 
based  on  these  observations  is  the  possibility  that  the  acute 
anaphylaxis  and  the  delayed  toxic  erythema  are  different  tjrpes 
of  reaction.  An  antianaphylaxis  which  was  developed  to  protect 
the  patient  against  the  former  failed  to  protect  against  the  latter 
complication.  The  influence  of  atropin  seemed  to  be  quite 
definitely  a  function  of  the  dosage,  and  doses  below  1/50  grain 
failed  to  protect  the  patient  against  shock. 

"Since  its  successful  employment  in  the  case  described,  we 
have  resorted  a  number  of  times  to  the  induction  of  antianaphy- 
laxis as  a  protection  against  acute  arsphenamine  reaction,  notably 
in  the  treatment  of  patients  with  tuberculids,  who  show  an 
idiosyncrasy  in  about  50  per  cent  of  the  cases.  I  have  noted 
with  interest  Danysz'  impression,  which  my  experience  confirms, 
that  small  preliminary  injections  'vaccinate'  the  susceptible 
patient,  so  to  speak,  against  the  larger  doses,  an  observation 
which  Danysz  supports  by  animal  experiment,  and  offers  likewise 
as  a  rationale  for  the  regulation  of  dosage  in  treatment,  and  a 
means  for  increasing  individual  tolerance  of  the  drug." 

Summary  of  Stokes'  Conclusions 

"The  acute  'nitritoid'  crisis  or  reaction  to  arsphenamine  is  a 
form  of  anaphylactic  shock,  explainable  on  physicochemical 
grounds  as  the  result  of  a  precipitation  either  of  the  drug  from 
its  colloidal  solution,  or  of  the  colloids  of  the  blood  plasma,  by 
the  drug,  or  by  an  impurity.  The  reaction  following  the  injection 
of  an  acid  or  only  partially  alkalinized  solution  of  arsphenamine 
either  too  rapidly  or  in  too  high  concentration  is  presumably  of 
the  same  type. 


REACTIONS  FOLLOWING  USE  OF  ARSPHENAMINE       91 

"The  nitritoid  crisis  can  apparently  be  inhibited  by  a  previous 
injection  of  atropin  (1/50  grain),  which  further  suggests  that  the 
reaction  is  a  form  of  anaphylactic  shock. 

"The  induction  of  antianaphylaxis  as  described  above  further 
supports  the  belief  that  the  nitritoid  crisis  is  a  form  of  anaphylac- 
tic shock. 

"The  induction  of  antianaphylaxis  in  patients  exhibiting  per- 
sistent idiosyncrasy  to  arsphenamine  or  neoarsphenamine  has 
proved  clinically  useful,  and,  as  a  means  of  increasing  their 
tolerance  of  the  drug,  deserves  further  trial  and  study." 

Reactions  from  Faulty  Technic 

In  a  very  small  percentage  of  cases  a  temperature  may  be 
noted,  sometimes  running  as  high  as  103°.  This  may  or  may  not 
be  accompanied  by  pain,  nausea,  vomiting  and  purging.  These 
cases  were  especially  prevalent  several  years  ago  when  too  little 
attention  was  paid  to  the  gastro-intestinal  tract  and  to  the  fresh- 
ness of  the  distilled  water  and  the  sodium  hydroxid. 

Rest  in  bed,  pyramidon,  acetyl-salicylic  acid  and  liquid  diet 
will  promptly  restore  these  cases. 

Care  should  be  observed  in  subsequent  administrations,  the 
dose  should  be  smaller  and  these  patients  should  be  given  atropin, 
following  the  ideas  of  Stokes,  as  hereinbefore  set  forth.  Epine- 
phrin  given  hypodermically  will  usually  control  the  unpleasant 
after-effects  of  acute  reactions. 

Some  Late  Reactions 

Among  the  late  reactions  are  dermatitis  and  erythema,  some- 
times accompanied  by  renal  disturbance.  A  nephritis  may  also 
occur  without  any  of  the  noticable  dermatological  conditions. 

Icterus  occasionally  follows  the  administration  of  arsphena- 
mine. Much  trouble  was  experienced  in  France  with  the  French 
arsphenamine  and  so  much  jaundice  occurred  in  England  during 
the  war  that  special  studies  have  been  undertaken  to  locate  the 
cause  and  determine  a  cure. 

Whenever  chemicals  containing  ring  compounds  reach  the 


92  THE  TREATMENT  OF  SYPHILIS 

blood  stream,  certain  decompositions  take  place  yielding  com- 
pounds of  simpler  structure  which  in  turn  cause  a  marked  in- 
creased destruction  of  red  blood  corpuscles.  These  changes  take 
place  in  from  two  to  twelve  hours  and  they  in  turn  change  the 
bile  secretion,  due  to  the  clogging  of  the  fine  bile  ducts  and  fol- 
lowed by  inflammatory  and  hemorrhagic  conditions. 

This  happens  when  there  is  a  hemolysis  in  the  blood  stream 
and  this  is  one  of  the  objections  to  the  use  of  concentrated  ar- 
senical solutions.  In  addition  dermatitis  exfoHativa  may  follow 
the  use  of  the  concentrated  solution.  Dr.  C.  N.  Myers,  U.  S. 
PubUc  Health  Service,  has  demonstrated  this  last  statement  in 
about  i,ooo  cases,  using  the  same  material  for  the  more  dilute 
solutions  as  well  as  for  the  concentrated  solutions.  The  der- 
matitis occurred  frequently  with  the  concentrated  solutions  and 
not  a  single  case  in  the  more  dilute. 

The  Herxheimer  Reaction 

Another  very  rare  symptom  is  the  Herxheimer  reaction.  The 
liberation  of  endotoxins  may  cause  symptoms  of  pressure,  or 
some  impairment  of  function.  The  Herxheimer  is  ordinarily 
noticed  in  connection  with  beginning  brain  lesions,  although  re- 
actions of  a  similar  nature  occur  when  lesions  of  the  circulatory 
system  or  of  the  viscera  are  present. 

Great  care  should  be  exercised  in  the  use  of  arsphenamine  in 
cases  such  as  described,  and  it  is  well  to  employ  mercury  or  the 
iodides  freely  and  for  several  days  before  the  administration  of 
salvarsan.  Careful  physical  examination  will  guard  against 
trouble  in  this  connection. 

Nerve  Disturbances 

Other  so-called  reactions  are  disturbances  of  the  ocular, 
auditory  and  other  nerves.  These  are  generally  indications  of 
the  activities  of  the  syphilitic  lesions  and  demonstrate  the  neces- 
sity for  further  arsenical  treatment.  For  example,  Benario  ob- 
served an  involvement  of  the  auditory  nerve  in  62  cases  out  of 
14,000  treated  by  him  with  salvarsan.    The  deafness  was  tem- 


REACTIONS  FOLLOWING  USE  OF  ARSPHENAMINE      93 

porary  and  disappeared  as  soon  as  the  antisyphilitic  treatment 
was  discontinued. 

Jacobsen  (Ugesk.  for  Lceger,  Copenhagen,  March  13,  1919) 
discusses  four  cases  of  syphilis  in  the  auditory  nerve  or  labyrinth 
in  which  sudden  deafness,  ear  noises  or  vertigo  and  vomiting  were 
the  symptoms  of  reaction,  showing  that  lues  had  invaded  the 
ear  or  that  the  drugs  had  caused  a  reaction.  He  says  (/.  A .  M. 
A.,  May  10,  191 9)  "analysis  of  these  and  similar  cases  on  record 
seems  to  show  that  part  of  the  neurorecurrences  are  due  to  a 
Herxheimer  reaction  to  arsphenamine.  This  reaction  congestion 
in  a  nerve  confined  in  a  narrow  passage  through  bone  injures  the 
nerve  and  may  cause  permanent  trouble.  But  the  majority  of 
cases  of  disturbances  in  the  auditory  nerve  are  the  result  of 
actual  damage  from  the  syphilis,  combined  with  or  possibly 
secondary  to  a  syphilitic  meningitis.  There  may  possibly  be  also 
a  small  contingent  of  cases  in  which  the  nerve  is  suffering  from  a 
direct  toxic  action  from  the  arsphenamine.  Even  in  persons 
with  normal  ears,  special  care  should  be  exercised  in  giving 
arsphenamine;  during  the  exanthem  stage  or  a  little  before  this, 
it  is  wiser  to  give  the  arsphenamine  only  in  combination  with 
mercury." 

Very  occasional  symptoms,  which  are  designated  under  the 
anaphylactic  group,  are  coryza,  sore  throat,  urticaria,  indigestion 
and  diarrhea,  but  they  are  as  fleeting  as  they  are  uncommon. 

The  Causes  of  Reactions 

Without  doubt,  there  are  numerous  causes  for  reactions. 

Wassermann  blames  the  bacterial  proteins  in  the  water; 
Wechselmann,  the  rapid  dissolution  of  great  quantities  of  spi- 
rochetes and  the  freeing  of  their  constituent  parts.  Some  ascribe 
reactions  to  the  "setting  free  of  some  toxic  substances  from  the 
spirochete,"  or  to  the  "liberation  of  endotoxins  from  the  killed 
organisms,"  or  to  impurities  in  the  drug  itself. 

Without  doubt,  each  reason  is  tenable  and  reactions  might  be 
caused  even  by  two  of  the  reasons  ascribed  acting  simultaneously. 
We  are  convinced,  however,  after  a  large  experience  in  the  ad- 
ministration  of   arsphenamine,    that   the   febrile   and   gastro- 


94  THE  TREATMENT  OF  SYPHILIS 

intestinal  disturbances  which  may  follow  the  injection  will  be 
found  due  to  one  or  more  of  these  causes : 

(a)  Dissolving  the  arsphenamine  in  warm  or  in  hot  water. 

(b)  Failure  to  use  fresh  double  distilled  water. 

(c)  Too  hurried  introduction  of  the  solution  into  the  circulation. 

(d)  Failure  to  dissolve  thoroughly  the  arsphenamine  in  water 
before  adding  the  salt  solution. 

(e)  Adding  the  sodium  hydroxid  solution  after  the  salt  solu- 
tion has  been  mixed  with  the  arsphenamine  solution,  instead  of 
before,  thus  producing  a  turbid  solution. 

(f)  Failure  to  use  the  sodium  hydroxid  in  the  proper  propor- 
tions and  manner. 

(g)  Failure  to  filter  the  completed  mixture  before  using. 

(h)  Using  gauze  for  filtering  purposes  that  contains  shreds 
which  pass  through  with  the  mixture. 

(i)  The  use  of  impure  chemicals. 

(j)  Failure  to  prove  that  the  arsphenamine  solution  was 
sufficiently  alkaline. 

(k)  A  cracked  ampule,  permitting  the  access  of  air  and  a 
consequent  oxidation  of  the  drug. 

(1)  Unclean  apparatus. 

(m)  Piercing  the  wall  of  the  vein  on  the  side  opposite  to  the 
needle's  point  of  entrance,  thus  infiltrating  the  tissues  with  the 
mixture,  and  causing  local  disturbances. 

(n)  Using  an  excessive  dose,  or  too  frequent  administration  of 
large  doses. 

(o)  Too  long  delay  after  preparation  in  using  the  mixture. 

(p)  Idiosyncrasy  of  the  patient  against  arsenic  preparations. 

(q)  Non-recognition  of  the  physical  condition  of  the  patient, 
who  may  have  had  a  disease  or  diseases  which  contraindicate 
the  uses  of  arsenic  compounds. 

Summarized,  imperfections  in  the  technic  of  the  operator  or 
his  failure  to  prepare  properly  his  patient  for  treatment  with 
arsphenamine. 

Undue  Caution  may  be  Harmful  to  Patient 
Many  physicians  are  unduly  cautious  regarding  the  so-called 


REACTIONS  FOLLOWING  USE  OF  ARSPHENAMINE      95 

reactions  occurring  during  salvarsan  injections,  and  interpret 
minor  symptoms  so  seriously  that  the  patient  is  oftentimes 
needlessly  denied  the  benefit  of  arsphenamine  treatment  because 
of  the  over-anxiety  of  the  administrator. 

We  have  seen  physicians  stop  an  injection  the  moment  a 
slight  flushing  of  the  conjunctiva  was  observed.  In  some  in- 
stances flushing  is  premonitory  of  trouble,  but  generally  such  a 
sign  possesses  no  significance. 

If  the  operator  will  watch  the  heart  through  the  pulse  he  will 
have  an  excellent  guide  to  his  further  procedure. 

In  initial  cases  the  pulse  may  go  to  100  or  even  higher  owing 
to  the  nervousness  of  the  patient  and  the  sting  from  the  intro- 
duction of  the  needle,  but  when  the  patient  is  reassured  it  shortly 
resimies  its  normal  rate.  In  a  recent  series  of  100  cases  with  one 
or  more  injections  there  was  practically  no  variation  in  the  pulse 
rate  sufficient  to  cause  the  slightest  unrest  on  the  part  of  the 
physician. 

The  Importance  of  Heavy  Dilutions  and  Slow  Injections 

We  have  urged  for  several  years  in  our  writings  on  s)^hilis 
and  its  treatment  by  salvarsan  and  mercury,  that  the  technic 
of  preparation  and  administration  as  laid  down  by  the  discoverer 
of  the  drug  should  be  employed. 

Unfortunately  too  many  physicians  have  attempted  to  im- 
prove on  the  technic,  with  the  result  that  the  patient  is  ofttimes 
the  sufferer. 

We  have  laid  especial  emphasis  on  heavy  dilutions  and  the 
necessity  for  slowness  of  entrance  of  the  well-diluted  drug  into 
the  circulation.  We  have  also  strongly  advised  the  immersion 
of  the  salvarsan  ampules  in  95  per  cent  alcohol,  so  that  any 
minute  crack  in  the  glass  may  be  detected.  Cracks  hardly 
visable  to  the  naked  eye  permit  oxidation,  and  if  undiscovered, 
cause  consequent  reactions.  Many  physicians  have  immersed 
the  ampules  in  water,  but  the  size  of  water  molecules  is  too  great 
to  permit  of  entrance  through  very  minute  cracks. 

It  is  a  pleasure,  therefore,  to  observe  that  the  United  States 
Public  Health  Service,  through  the  capable  director  of  its  Hy- 


96  THE  TREATMENT  OF  SYPHILIS 

gienic  Laboratory  in  Washington,  Dr.  George  W.  McCoy,  has 
publicly  directed  attention  to  the  absolute  necessity  of  carrying 
out  these  important  details.  He  makes  a  statement  which  many 
of  us  have  believed  and  preached  for  years,  that  "any  physician 
who  fails  to  observe  these  precautions  should  be  considered  as 
directly  responsible  for  serious  results  that  follow  the  improper 
use  of  the  drug." 

U.  S.  Public  Health  Service  on  Concentration  and  Rapidity  of 

Administration 

A  few  feeble  voices  in  the  wilderness  avail  little,  but  a  voice 
speaking  with  authority  is  clearly  heard  over  the  clamorous  tu- 
mults of  the  multitude.  The  profession  has  every  reason  to  con- 
gratulate itself  that  Dr.  McCoy  has  directed  the  attention  of 
arsphenamine  users,  present  and  prospective,  to  the  absolute 
imperativeness  of  careful  and  proper  technic,  and,  unless  aU 
signs  fail,  it  will  not  be  long  before  the  reactions  following  ar- 
sphenamine injections  will  be  but  a  memory. 

Dr.  McCoy  made  known  his  dictum  through  a  letter  published 
in  the  weekly  medical  journals  of  May  lo,  1919,  which  reads: 

"It  appears  that  there  is  a  lamentable  want  of  care  on  the  part 
of  many  physicians  who  administer  arsphenamine  as  to  the  con- 
centration of  the  drug  used  and  the  time  required  for  adminis- 
tration. 

"The  Hygienic  Laboratory  receives  many  complaints  in 
regard  to  untoward  results  from  the  administration  of  arsphen- 
amine made  by  various  American  producers.  When  careful 
investigation  is  made  it  is  almost  invariably  found  that  the  drug 
has  been  used  in  a  solution  that  is  too  concentrated,  and  that 
it  has  been  administered  too  rapidly.  We  have  reports  of  a 
dose  of  0.4  gm.  being  given  in  a  volume  of  as  little  as  25  c.  c. 
and  injected  within  thirty  seconds.  Such  practice  is  abuse,  not 
use,  of  a  powerful  therapeutic  agent. 

"If,  in  addition  to  the  usual  precautions  as  to  the  use  of  perfect 
ampules  and  neutralization,  physicians  would  give  the  drug  in 
concentration  of  not  more  than  o.i  gm.  to  30  c.  c.  of  fluid  and 


REACTIONS  FOLLOWING  USE  OF  ARSPHENAMINE      97 

allow  a  minimum  of  two  minutes  for  the  intravenous  injection 
of  each  o,  i  gm.  of  the  drug  (in  30  c.  c.  of  solution)  the  number 
of  reactions  would  be  very  materially  reduced.  This  would  neces- 
sitate from  30  to  180  c.  c.  of  the  solution  for  the  doses  usually 
given  and  would  require  from  six  to  twelve  minutes  for  the  in- 
jection. 

"Any  physician  who  fails  to  observe  these  precautions  should 
be  considered  as  directly  responsible  for  serious  results  that 
follow  the  improper  use  of  the  drug." 

The  Journal  of  the  American  Medical  Association,  under  the 
caption  "The  Administration  of  Arsphenamine,"  had  this  to 
say  editorially  (p.  1372): 

"Elsewhere  in  this  issue  appears  a  letter  from  Dr.  George  W. 
McCoy,  director  of  the  hygienic  laboratory  of  the  United  States 
Public  Health  Service,  concerning  two  special  points  in  the  ad- 
ministration of  arsphenamine,  namely,  the  dilution  and  the 
rapidity  of  administration.  His  letter  is  followed  by  a  circular 
issued  by  the  Public  Health  Service  to  all  its  officers  covering 
the  same  general  subject.  Numerous  disagreeable  results  fol- 
lowing the  use  of  the  various  preparations  of  arsphenamine 
have  led  research  workers  to  make  a  special  study  of  the  cause 
of  these  accidents.  Such  studies  have  indicated  that  most  of  the 
disagreeable  results  are  not  inherent  in  the  preparations  them- 
selves, but  are  produced  through  faulty  steps  in  the  adminis- 
tration of  the  remedies.  The  suggestions  made  in  the  circular 
of  the  Public  Health  Service,  if  followed  by  physicians,  will  aid 
in  preventing  repetition  of  disagreeable  after  effects." 

The  Journal  appends  this  note  to  Dr.  McCoy's  letter: 

"The  United  States  Public  Health  Service  has  issued  a  cir- 
cular to  its  officers  concerning  the  proper  mode  of  administering 
these  preparations.  It  is  appropriate  to  reproduce  this  circular 
in  connection  with  the  letter  of  Dr.  McCoy.  Careful  attention 
to  the  letter  and  the  following  points  from  the  circular  men- 
tioned will  undoubtedly  reduce  the  number  of  reactions  following 
the  use  of  arsphenamine  preparations." 


98  THE  TREATMENT  OF  SYPHILIS 

The  circular  issued  by  the  United  States  Public  Health  Serv- 
ice to  its  surgeons  is  presented  herewith: 


ADMINISTRATION  OF  ARSPHENAMINE  AND  NEO- 
ARSPHENAMINE 

TREASURY  DEPARTMENT 

Bureau  of  the 

United  States  Public  Health  Service 

Washington,  April  28,  1919. 
Bureau  Circular 
Letter  No.  163. 

Medical  Officers,  U.  S.  Public  Health  Service, 
and  others  concerned: 

In  view  of  the  variations  of  technique  6f  the  administration  of  arsphen- 
amine  and  neo-arsphenamine  at  various  Service  clinics,  attention  is  invited 
to  the  following  points,  careful  observation  of  which  should  reduce  the 
number  of  reactions  from  the  use  of  this  drug. 

The  ampule,  before  opening,  should  be  immersed  in  95%  alcohol  for 
fifteen  minutes,  so  as  to  detect  any  crack  or  aperture  not  primarily  recog- 
nizable. (Should  such  a  breach  be  discovered,  the  contents  of  the  ampule 
should  be  discarded.) 

ARSPHENAMINE 

(i)  Solution:  Cold,  boiled,  freshly  distilled  water  should  be  used  in  all 
cases  except  in  the  case  of  "arsenobenzol"  made  by  the  Dermatological 
Research  Laboratory,  in  which  case  hot  water  is  required.  No  more  solu- 
tion should  be  prepared  at  one  time  than  can  be  given  in  30  minutes. 

(2)  Neutralization  and  alkaUnization  of  the  above  solution:  With  a 
graduated  pipette  or  burette  add  0.9  cc.  of  Normal  NaOH  for  each  o.i 
gm.  of  the  drug  (i.  e.,  5.4  cc.  for  each  0.6  gm.).  The  alkaU  should  be  added 
aU  at  once  and  should  quickly  convert  the  acid  salt  solution  of  arsphenamine 
into  the  alkaline  salt  solution,  or  the  disodium  of  salt  of  the  arsphenamine 
base.  The  solution  of  arsenobenzol,  which  is  hot,  should  be  cooled  before 
adding  the  alkali.  This  represents  slightly  more  alkaU  than  just  enough  to 
re-dissolve  the  precipitate  formed  by  the  addition  of  this  reagent. 

The  alkaU  used  should  be  standardized  against  normal  acid.  Normal 
NaOH  is  a  4%  solution  of  the  c.  p.  product.   However,  if  made  on  the  basis 


REACTIONS  FOLLOWING  USE  OF  ARSPHENAMINE       99 

of  weight,  it  may  be  considerably  less  than  this  strength,  hence  the  necessity 
for  titration.  It  could  be  made  up  in  amount  suflBcient  for  a  month's  use, 
if  kept  in  a  well-stoppered  bottle  and  exposed  to  the  air  for  only  a  few 
seconds  at  a  time  when  using  the  solution.  It  should  be  kept  in  a  bottle 
that  has  been  used  for  NaOH  solution  for  some  time  so  that  all  action  it 
might  cause  on  the  glass  has  already  occurred.  Where  it  is  impossible  to 
have  this  made  up  at  the  station,  it  will  be  furnished  upon  request  from  the 
Hygienic  Laboratory.  Should  the  NaOH  solution  become  cloudy  or  con- 
tain a  precipitate,  it  should  be  discarded. 

(3)  Concentration  of  the  Drug:  It  is  desired  to  emphasize  the  fact  that 
the  concentration  of  the  drug  should  not  be  greater  than  o.i  gm.  to  30  cc. 
of  final  solution.  The  practice  of  using  concentrated  solution  is  not  only 
in  direct  conflict  with  the  instructions  on  the  circular,  but  carries  a  distinct 
hazard  to  the  patient. 

(4)  Method  of  Injection:  The  gravity  method  only  should  be  used. 
Where  several  patients  are  to  be  injected  from  the  same  solution,  the  con- 
tainer of  the  solution  should  be  graduated.  If  not  already  graduated,  this 
can  be  done  in  a  few  minutes  by  sticking  on  a  strip  of  adhesive  plaster  and 
marking  the  graduations  on  this.  A  convenient  way  to  do  this  is  to  have 
each  mark  represent  30  cc.  with  a  long  mark  for  each  180  cc;  then,  if  the 
volume  is  made  up  so  that  each  o.i  gm.  of  drug  is  contained  in  each  30  cc, 
the  doses  can  be  given  accurately.  It  is  a  great  convenience  to  have  a 
glass  stop-cock  near  the  glass  tubing  which  serves  as  a  window  just  above 
the  needle  in  order  to  control  the  rate  of  injection.  If  no  stopcocks  are  at 
hand,  the  rate  can  be  controlled  by  the  size  of  the  needle  and  the  height  of 
the  column  of  fluid.    A  No.  18  or  20  B.  &  S.  gauge  is  the  best  size  needle. 

(5)  Rate  of  injection:  Operators  shoxild  pay  particular  attention  to  the 
rate  of  administration  and  in  no  case  exceed  0.1  gm.  of  drug  (30  cc.  of  solu- 
tion) in  2  minutes.  This  point  is  especially  emphasized  because  it  is  be- 
lieved that  excessive  rapidity  of  administration  accounts  for  more  imfavor- 
able  results  in  the  use  of  arsphenamine  than  any  other  one  thing. 

NEO-ARSPHENAMINE 

The  principal  precautions  to  be  observed  in  the  administration  of  neo- 
arsphenamine  are: 

(i)  But  a  single  ampule  should  be  dissolved  at  a  time.    This  drug  must 
not  be  dissolved  in  bulk  to  be  given  to  a  series  of  patients. 

(2)  Cold  water  only  should  be  used. 

(3)  The  dilution  should  be  not  stronger  than  0.1  gm.  of  the  drug  in  2  c  c. 
of  freshly  distflled  water. 

(4)  A  very  small  needle  should  be  used,  and  the  time  of  injection  of  the 
dose  should  be  not  less  than  five  minutes. 


lOO  THE  TREATMENT  OF  SYPHILIS 

CAUTION 

Operators  are  advised  that  they  will  be  held  responsible  for  untoward 
results  following  the  use  of  arsphenamine  and  neo-arsphenamine  in  cases 
where  there  has  been  material  deviation  from  the  outline  given  above. 
Acknowledgment  of  receipt  of  this  letter  is  directed. 

Respectfully, 

Rupert  Blue, 
Surgeon  General. 
Accidents 

Serious  accidents  practically  never  follow  the  proper  intro- 
duction of  a  properly  prepared  arsphenamine  solution  into  the 
circulation,  i.  e.,  when  the  physician's  technic  is  perfect.  There 
is  no  reason  why  perfection  should  not  be  attained,  particularly 
when  we  consider  that  faulty  technic  endangers  human  life. 

A  common  accident  is  the  penetration  of  the  vein  at  a  point 
opposite  the  proper  place  of  entrance  of  the  needle.  As  a  result, 
the  solution  leaks  into  the  surrounding  tissue  and  the  infiltration 
may  develop  a  badly  inflamed  arm  and  a  possible  abscess  with 
sloughing.  Such  an  occurrence  can  be  obviated  by  using  a  short 
beveled  needle,  and  by  first  introducing  sterile  distilled  water 
into  the  vein,  until  the  operator  is  certain  the  flow  is  free  and  the 
needle  properly  in  the  vein. 

Acidity  of  the  solution  may  bring  about  a  phlebitis,  with  its 
attendant  difficulties. 

Over-alkalinity  of  the  solution  may  result  in  the  formation  of 
a  thrombus,  which  will  enter  the  circulation.  Wounding  of  the 
vein  may  also  cause  a  thrombus. 

Dr.  Loyd  Thompson  of  Hot  Springs,  Arkansas,  reports  (Syph- 
ilis, p.  238,  1916)  the  case  of  a  physician  who,  finding  that  the 
blood  did  not  flow  freely  through  a  needle  inserted  in  an  elbow 
vein,  opened  up  the  lumen  of  the  needle  with  its  stylet.  A  blood 
clot  was  undoubtedly  pushed  out  of  the  needle  into  the  vein,  as 
the  patient  died  before  the  solution  was  administered. 

Embolism  may  also  follow  the  introduction  of  air  into  the  vein 
on  account  of  the  failure  of  the  operator  to  drive  all  the  air  out  of 
the  cyhnders  and  tubing. 


REACTIONS   FOLLOWING  USE  OF  ARSPHENAMINE     loi 

Embolism  may  be  caused  by  bits  of  cotton  which  enter  the 
solution  while  it  is  being  filtered. 

The  Importance  of  Watching  the  Kidneys 

Patients  have  died  during  or  soon  after  the  administration  of 
arsphenamine.  We  believe  that  in  the  majority  of  instances  the 
fault  is  that  of  the  operator,  in  that  some  important  essential 
was  overlooked.  A  physical  examination  of  the  patient,  often 
neglected,  might  have  revealed  some  contraindication. 

Urinary  examinations  are  too  seldom  made  by  many  physicians 
administering  arsphenamine,  who,  forgetting  this  essential,  can 
only  trust  to  good  fortune  that  the  kidneys  of  their  patients  are 
in  the  proper  condition  to  eliminate  the  arsenic. 

Dr.  E.  L.  Keyes,  Jr.,  of  New  York  {Urology,  p.  829,  1917)  is 
of  the  opinion  that  acute  congestion  of  the  kidneys  is  the  most 
common  cause  of  death.  He  gives  acute  encephalitis  as  another 
casus  morti. 

He  advocates  a  careful  examination  of  kidneys  and  urine,  and 
advises  that  if  the  urine  reveals  albumin  and  casts  and  if  it 
shows  a  deficient  excretion  of  urea  the  physician  inject  only  a 
third  or  a  fourth  of  the  usual  dose  of  arsphenamine. 

Col.  E,  B.  Vedder,  U.  S.  Army  (Syphilis  and  the  Public  Health, 
p.  287,  191 8)  lays  particular  emphasis  on  the  condition  of  the 
kidneys  at  the  time  of  treatment.  He  notes  that  in  fatahties 
occurring  in  patients  in  the  active  secondaries  two  or  three  days 
after  the  injection,  they  presented  symptoms  resembling  uremia. 
He  observes  that  in  three  and  one  half  years  four  fatalities  oc- 
curred in  over  3 1 ,000  injections  and  that  three  of  the  four  cases 
on  autopsy  revealed  an  intense  acute  nephritis. 

Wechselmann  {The  Pathogenesis  of  Salvarsan  Fatalities,  St. 
Louis,  1 913)  believes  that  some  deaths  following  the  use  of  sal- 
varsan are  due  to  previous  injuries  by  mercury  to  the  kidneys, 
which  are  thus  unable  to  eliminate  the  arsenic. 

Animal  Experiments  Reveal  Interesting  Facts 

Fatalities  follow  in  an  exceeding  small  percentage  of  cases. 
The  percentage  is,  doubtless,  between  1/50  and  i/ioo  of  i  per 


I02  THE  TREATMENT  OF  SYPHILIS 

cent,  a  number  almost  negligible.  Such  a  factor  must,  however, 
be  considered,  and  we  are,  therefore,  interested  in  some  of  the 
animal  experiments  of  D.  E.  Jackson  and  M.  I.  Smith  of  the 
Division  of  Pharmacology  of  the  Hygienic  Laboratory,  United 
States  Public  Health  Service.  {Jour.  Phar.  and  Exper.  Therap., 
Vol.  Xn,  No.  4,  1918.)  They  made  an  analysis  of  the  effects  of 
various  arsphenamine  preparations  on  the  cardio-vascular  ap- 
paratus for  the  purpose  of  ascertaining  the  cause  of  acute  reac- 
tions, and  examined  various  remedies  in  the  search  for  an  efficient 
method  of  treating  acute  collapse  from  the  drug. 

Alkaline  solutions  were  used.  When  a  dose,  averaging  the 
amount  usually  used  in  the  clinic  at  the  Hygienic  Laboratory, 
was  injected  slowly  there  was  little  or  no  immediate  cardio- 
vascular change  observed,  but  acceleration  of  the  injection  rate 
and  an  increase  in  the  dose  produced  definite  effects.  The  first 
of  these  was  a  slight  but  gradually  progressive  dilatation  of  the 
heart  and  a  slow  fall  of  blood  pressure. 

A  rapid  injection,  it  should  be  noted,  is  likely  to  cause  a  rather 
marked,  sudden  fall  of  blood  pressure. 

Large  doses  of  arsphenamine  caused  a  variety  of  vascular 
reactions  of  the  internal  organs,  such  as  dilatation  of  the  spleen, 
contraction  of  the  kidney  and  dilatation  of  the  intestinal  vessels. 

Further  experimentation  demonstrated  that  if  a  dose  of 
30  mgm.  per  Idlo  of  a  2  per  cent  arsphenamine  solution  were  in- 
jected in  a  dog  rapidly,  i.  e.,  within  three  or  four  minutes,  the 
pulmonary  blood  pressure  might  be  increased  100  per  cent  or 
more  and  a  marked  fall  in  systemic  blood  pressure  was  likely 
to  occur. 

The  authors  feel  that  under  the  unusual  conditions  under 
which  the  heart  must  work  when  enormous  rises  in  pulmonary 
blood  pressure  are  produced  by  large  doses  of  the  drug,  the  heart 
may  be  so  strained  that  delirium  cordis  may  well  be  expected. 

They  are  of  the  opinion  that  the  alkalinity  of  the  arsphenamine 
solution  alone  may  be  responsible  for  a  considerable  degree  of 
rise  in  pulmonary  blood  pressure,  but  they  also  believe  that  the 
specific  action  of  the  arsenic  compound  is  responsible  for  part 
and  may  be  most  of  the  increase  in  pulmonary  arterial  tension. 


REACTIONS  FOLLOWING  USE  OF  ARSPHENAMINE     103 

They  emphasize  the  fact  that  rise  in  puhnonary  pressure  was 
observed  only  when  large  doses  of  the  drug  were  injected. 

They  further  state  that,  while  large  doses  of  concentrated 
alkaline  solutions  rapidly  injected  always  produced  marked  rises 
in  pulmonary  blood  pressure,  slow  injections  of  dilute  solutions 
brought  about  no  visible  rise  in  pulmonary  pressure. 

Important  Role  Played  by  Disturbance  of  Pulmonary  Circulation 

Jackson  and  Smith  are,  therefore,  led  to  the  belief  that  a 
disturbance  of  pulmonary  circulation  is  one  of  the  chief  factors 
when  patients  complain  of  faintness,  dyspnea  and  circulatory 
disturbances. 

Moderate  doses  of  a  good  arsphenamine  preparation  slowly 
injected  produced  but  little  effect  on  the  respiration,  but  as  the 
action  of  a  large  dose  developed  the  respiration  became  slower 
and  shallower. 

Respiratory  embarrassment  is  the  result  of  depression  of  the 
respiratory  center  and  of  a  greatly  depressed  circulation.  Artifi- 
cial respiration  proved  of  no  avail. 

In  experimental  arsphenamine  intoxication,  Jackson  and 
Smith  found  that  respiratory  failure  was  probably  the  immediate 
cause  of  death,  as  the  heart  usually  beat  a  short  time  after 
breathing  ceased. 

If  a  rapid  injection  of  a  toxic  preparation  was  given  frequently 
the  heart  and  respiration  stopped  simultaneously. 

The  experimenters,  in  their  search  for  the  trouble-making 
properties,  carefully  went  into  the  effects  produced  by  the  inter- 
mediary and  oxidation  products  which  are  formed  in  the  process 
of  manufacture  of  arsphenamine,  but  they  were  satisfied  that 
none  of  these  play  a  significant  role  in  acute  toxic  action. 

Danysz  {Ann.  de  Vlnst.  Pasteur,  Paris,  No.  3,  p.  114,  1917) 
believes  that  arsphenamine  in  alkaline  solutions  may  undergo 
precipitation  in  the  blood  stream,  thus  forming  insoluble  masses 
which  tend  to  lodge  in  the  smaller  blood  vessels,  especially  in  the 
puhnonary  vessels,  thus  giving  rise  to  serious  symptoms.  He 
thinks  that  later  these  insoluble  masses  again  undergo  solution, 
due  to  the  solvent  action  of  the  blood  and  tissue  juices,  which, 


I04  THE  TREATMENT  OF  SYPHILIS 

combining  with  the  masses  of  arsphenamine,  form  soluble, 
organic  compounds  which  are  carried  by  the  blood  stream  to  the 
tissues  of  the  body- 
Jackson  and  Smith  endeavored  by  a  series  of  experiments  to 
corroborate  this  theory,  but  without  success.  They  found  the 
toxicity  of  arsphenamine  was  not  effected,  nor  could  they  demon- 
strate with  alkaline  solutions  that  precipitation  and  embolism 
occurred. 

The  Use  of  Tyramine  in  Cases  of  Collapse 

For  the  treatment  of  acute  arsphenamine  collapse  Jackson  and 
Smith  suggest  tyramine  (parahydroxyphenylethylamine)  which 
can  be  given  intravenously  in  time  of  emergency  or  intramuscu- 
larly or  subcutaneously.  They  say  they  have  prolonged  the 
Hves  of  animals  severely  poisoned  with  arsphenamine  by  intro- 
ducing intravenously  lo  mgm.  of  tyramine  into  animals  weighing 
from  5  to  lo  kilos.  The  drug  stimulates  the  heart  and  produces  a 
prolonged  and  sustained  rise  in  systemic  blood  pressure.  The 
effects  of  tyramine  progressively  decrease  after  the  initial  rise  in 
pressure,  which  requires  from  one  to  five  or  more  minutes  for  its 
full  development.  The  investigators  say  the  systemic  pressure 
does  not  rise  so  high  and  the  danger  of  acute  dilatation  of  the 
heart  is  not  so  great  as  with  the  intravenous  injection  of  epineph- 
rin,  but  the  effects  of  tyramine  are  much  more  lasting. 

Hewlett  (Arch.  Int.  Med.,  XXI,  411,  1918)  has  injected 
tyramine  hypodermically  in  doses  of  40  to  80  mgm.  with  an 
average  of  60,  and  has  been  satisfied  with  it  as  a  blood-pressure 
raising  agent.    It  also  seems  to  improve  the  circulation. 

The  consensus  of  the  best  opinion  is  that  few  fatalities  result 
from  the  toxicity  of  the  arsphenamine  itself  but  that  the  results 
usually  come  from  imperfection  in  technic,  physical  inability  of 
the  patient  to  assimilate  arsenic  or  metabolic  changes  in  the 
system  not  as  yet  understood  by  physiologists. 


CHAPTER  XI 

3HE   WASSERMANN  REACTION  AZSTD   THE   EFFECTS   OF   TREATMENT 

THEREON 

The  Provocative  Wassermann  Reaction 

After  a  luetic  patient  is  beKeved  to  be  free  from  the  spirocheta 
pallida  it  is  the  practice  of  most  syphilologists  to  give  a  pro 
vocative  injection  of  salvarsan.  Gennerich  {Ber.  Klin.  Woch., 
1910,  No.  38)  reported  that  negative  Wassermann  reactions 
often  changed  to  positives  after  a  salvarsan  injection.  Thus  we 
are  able  to  demonstrate  the  effectiveness  of  our  treatment  by  a 
provocative  injection. 

Our  procedure  is  to  inject  0.3  salvarsan  intravenously  and 
have  a  Wassermann  done  every  day  thereafter  for  six  days,  by 
which  time  the  change  of  the  reaction  will  be  effected,  if  there  is 
any  cause  to  change.  It  is  well,  however,  to  have  Wassermanns 
also  done  on  the  8th,  loth,  12th  and  14th  days  after  the  pro- 
vocative injection,  as  the  reaction  may  be  unduly  delayed. 

If  spirochetEe  are  in  the  system  their  presence  will  probably 
be  made  known  by  this  method.  If  a  negative  Wassermann  re- 
mains negative  after  a  provocative  injection,  and  all  other 
standards  are  fully  m.et,  we  have  a  right  to  conclude  that  the 
patient  is  cured.     (See  pp.  152-153.) 

Drs.  John  H.  Stokes  and  Paul  A.  O'Leary  of  the  Mayo  Clinic 
in  an  enlightening  paper  on  this  subject  (Am.  Jour.  Syph.,  i,  629, 
191 7)  presents  these  indications  for  the  provocative  injection: 

"i.  A  definite  history  of  primary  or  secondary  lesions  or  a 
suspicious  genital  sore  of  any  description,  (With  a  negative 
Wassermann.) 

"2.  Syphihs  in  husband  or  wife  or  a  history  of  a  sore  in  either. 

"3.  Treated  cases  to  determine  the  fact  of  cure  or  need  for 
further  treatment.  One-third  of  the  cases  thus  tested  by  us, 
gave  a  positive  provocative  effect. 

"4.  Obscure  bone  or  joint  lesions. 


io6  THE  TREATMENT  OF  SYPHILIS 

"5.  Histories  of  miscarriages  unless  the  anatomical  cause  is 
glaringly  obvious. 

"6.  Mothers  of  syphihtic  children  without  clinical  signs  of  the 
disease. 

"7.  Cases  with  a  history  of  a  positive  Wassermann  elsewhere, 
negative  on  present  examination. 

"8.  Mental  deviates  and  constitutionally  inferior  individuals 
with  suspicious  histories. 

"9.  Certain  signs  elicited  by  special  examinations,  such  as 
decreased  bone  conduction  with  normal  hearing,  chorioretinitis 
and  retinitis  pigmentosa,  bilateral  dacryocystitis  in  childhood," 
etc. 

The  Effect  of  Arsphenamine  and  Mercury  upon  the  Wassermann 

Reaction 

A  careful  study  of  the  hterature  upon  this  subject  since  sal- 
varsan  first  appeared  shows  the  effect  of  the  fallacious  behef 
that  one  injection  will  completely  kill  all  the  treponemata  and 
cure  the  patient.  In  the  earlier  days  many  cases  relapsed 
within  a  year  because  mercurial  treatment  had  not  been  used 
in  conjunction  with  salvarsan  or  on  account  of  too  little  treat- 
ment. 

Today,  when  we  realize  that  the  system  must  be  flooded  with 
anti-luetic  agents,  the  number  of  cases  relapsing  has  been  re- 
duced to  a  minimum. 

In  acute  cases,  treated  before  the  Wassermann  has  become 
positive,  we  are  usually  able  to  keep  it  negative  if  vigorous  treat- 
ment is  employed. 

In  acute  cases  in  which  the  first  examination  reveals  a  positive 
reaction,  regular  salvarsan  treatments  and  mercury  injections 
generally  change  the  positive  to  a  negative  in  from  four  to  eight 
weeks. 

When  primary  cases  are  treated,  as  is  our  custom,  with  eight 
injections  of  arsphenamine,  at  from  five  to  seven  day  intervals, 
and  with  mercurial  injections  or  inunctions  for  twelve  weeks, 
the  chances  strongly  favor  a  continuous  negative  reaction,  unless 
something  unforeseen  occurs. 


THE  WASSERMANN  REACTION  107 

In  cases  of  long  standing,  several  courses  may  be  necessary 
to  change  the  reaction.  One  of  our  cases,  a  man  sixty-four 
years  old,  with  a  history  of  luetic  infection  twenty-one  years 
before  presenting  himself  to  us,  took  seven  courses,  with  the  usual 
amount  of  mercury,  before  a  negative  reaction  was  obtained. 
The  subsequent  results,  however,  justified  this  persistent  effort. 

The  consensus  of  opinion  is  that  conjoint  arsphenamine  and 
mercury  treatment,  faithfully  and  intelHgently  administered,  wiU 
usually  produce  a  negative  reaction  in  primary  positive  cases  in 
two  months  or  less,  and  that  in  long-standing  cases  consistent 
treatment  will  eventually  bring  about  a  permanent  negative  in  a 
majority  of  cases  except  in  those  aortic  or  cord  lesion  cases, 
which  are  irresistible  to  treatment  from  a  serological  standpoint. 

The  Definite  Serological  Effect  of  Arsphenamine 

Many  years  must  necessarily  elapse  before  we  can  say  with 
absolute  certainty  that  salvarsan  and  mercury  have  a  real  defi- 
nite and  lasting  action  upon  the  Wassermann  reaction. 

We  know  the  action  of  mercury  as  a  medicinal  agent,  for  it 
has  been  utilized  as  an  antiluetic  for  centuries. 

Since  the  Wassermann  reaction  became  known  the  medical 
profession  has  had  ample  opportunity  to  study  the  effect  of 
mercurial  treatment  in  connection  with  that  reaction. 

It  is,  however,  too  early  to  make  affirmative  statements  re- 
garding salvarsan's  permanent  effacement  of  the  positive  Wasser- 
mann. 

Experience  has  taught  us  that  mercury  has  not  been  the  ef- 
fective spirocheticide  that  our  medical  forebears  considered  it. 
Relapses  under  mercury  were  not  uncommon.  Many  an  un- 
fortunate syphilitic  was  lulled  into  security  by  the  disappearance 
of  outward  symptoms  under  mercury  and  its  accompanying 
medication,  only  to  awaken  after  a  period  of  years  to  the  hor- 
rible realization  of  tabes,  paresis  and  other  sequelae  which  are  the 
results  of  an  invasion  of  the  treponemata. 

We  indulge  the  hope  that  salvarsan  produces  a  more  per- 
manent effect  on  the  system  and  that  relapses  will  be  less  com- 


io8  THE  TREATMENT  OF  SYPHILIS 

mon  following  its  proper  use,  but  sufficient  time  has  not  elapsed 
to  verify  this  hope  sufficiently  to  make  it  an  undisputed  fact. 
However,  as  Col.  Charles  F.  Craig,  U.  S.  Army,  well  says,  it  has 
been  demonstrated  that  in  the  treatment  of  lues  mercury  is  of 
small  value,  when  compared  with  salvarsan. 

He  states  {The  Wassermann  Test,  1918,  p.  184)  "for  one  case 
that  becomes  negative  after  treatment  with  mercury  there  are 
hundreds  that  become  negative  after  treatment  with  salvarsan, 
and  although  the  majority  of  both  classes  of  cases  relapse  in 
time  and  again  present  a  positive  Wassermann  reaction,  the 
relapses  are  much  less  frequent  among  patients  treated  with 
salvarsan  than  with  mercury." 

Positive  Results  from  Salvarsan  and  Mercury 

The  effect  of  salvarsan  and  mercury  upon  the  Wassermann  re- 
action is  not,  fortunately,  a  matter  of  conjecture. 

The  work  of  Craig  and  of  other  careful  observers  has  proved 
that  we  have  something  real  to  look  forward  to  as  a  result  of  the 
combination  of  these  two  antiluetics.    Craig  {iUd)  continues: 

"The  relative  efficiency  of  salvarsan  and  mercury  in  causing  a 
disappearance  of  the  Wassermann  reaction  is  well  illustrated  in 
patients  who  had  previously  been  treated  with  mercury  before 
receiving  salvarsan.  Of  90  patients  who  were  treated  with  mer- 
cury by  the  mouth  for  nine  months  or  more  before  the  adminis- 
tration of  salvarsan  and  who  gave  a  positive  Wassermann  re- 
action, 68,  or  70.5  per  cent  became  negative  within  eight  weeks 
after  the  administration  of  the  drug.  The  intensity  of  the  re- 
action at  the  time  of  receiving  salvarsan  and  the  length  of  time 
the  patients  had  been  taking  mercury  is  shown  in  this  table: 


THE  WASSERMANN  REACTION 


109 


The  Wassermann  Test  in  Patients  Who  Had  Taken  Mercury  for 
Various  Periods  of  Time  (After  Craig) 


Method  of 

Time  of 
Treatment 

Number 
of  Cases 

Character  of  the  Reaction 

Treatment 

+  + 

+ 

+  - 

Mercury  by  mouth 

U                   U             il 
CC                   ii             ii 

ei              (I          i( 

9  months 

1  year 

2  years 

3  years 

17 
26 

17 
8 

8 

16 

7 

3 

7 
8 

9 

4 

2 

2 
I 

I 

Totals 

68 

34 

28 

6 

"The  table  shows  that  26  of  these  patients  had  taken  mercury 
by  mouth  for  a  period  of  one  year  and  that  16  of  them  still  gave 
a  four  plus  reaction;  that  17  had  received  the  same  treatment  for 
two  years,  of  whom  7  still  gave  a  two  plus  reaction;  and  that  8 
had  received  treatment  for  three  years,  of  whom  3  still  gave  a  two 
plus  reaction.  Of  the  68  cases  not  one  had  become  negative  as 
the  result  of  mercury  administered  by  the  mouth,  but  after  the 
administration  of  salvarsan  every  one  became  negative  within  8 
weeks.  This  is  certainly  very  decisive  proof  of  the  greater  specific 
action  of  salvarsan  and  could  only  be  ascertained  by  the  effect 
of  the  drugs  in  question  upon  the  Wassermann  reaction. 

"Objection  may  be  raised  to  the  results  recorded  above  by 
calling  attention  to  the  fact  that  the  administration  of  mercury 
by  mouth  is  now  well  recognized  to  be  the  poorest  of  all  ways  of 
giving  this  drug,  although  it  is  not  so  long  ago  that  three  years ' 
treatment  by  mouth  with  mercury  was  considered  by  the  best 
authorities  upon  the  disease  as  adequate  for  the  cure  of  syphilis. 
In  answer  to  this  objection  another  table  is  given,  covering  18 
patients  treated  with  hypodermic  injections  of  mercury,  a  plan 
of  treatment  generally  acknowledged  to  be  the  most  efficient  of 
the  many  ways  of  administering  the  drug.  For  purposes  of  com- 
parison the  effect  upon  the  Wassermann  of  treatment  with  sal- 
varsan is  also  included. 


no 


THE  TREATMENT  OF  SYPHILIS 


The  Comparative  Results  of  Treatment  with  Mercury  and  Salvaesan 

UPON  THE  WaSSERMANN  REACTION   (AeTER   CrAIG) 


Number  oj 

Mercurial  Treatment 

Salvarsan  Treatment 

■^■^ 

Cases 

Injections  of 

Character  of 

Dose  0.6  gm. 

Character  of 

Gray  Oil 

Reaction 

Reaction 

2 

7 

+  + 

Intramuscular 

— 

8 

+ 

a              ic 

— 

9 

+  + 

il                ic 

— 

II 

+  + 

ic               n 

— 

IS 

+  + 

Intravenous 

— 

15 

+ 

Intramuscular 

— 

i8 

++ 

a              li 

— 

19 

++ 

Intravenous 

— 

20 

++ 

li              a 

— 

25 

+ 

Intramuscular 

— 

3° 

+ 

iC                     li 

— 

"From  a  consideration  of  this  table  it  is  evident  that  cases 
having  had  as  many  as  i8  to  20  injections  of  gray  oil  still  gave  a 
two  plus  Wassermann  reaction  and  that  cases  having  as  high  as 
25  and  30  injections  still  gave  a  three  plus  reaction.  After  the 
administration  of  salvarsan  all  became  negative  within  8  weeks, 
and  in  12  of  the  cases  only  one  intramuscular  injection  of  0.6 
gm.  of  salvarsan  was  administered.  While  there  is  reason  to 
believe  that  previous  treatment  with  mercury  may  have  had 
something  to  do  with  the  good  effects  produced  by  salvarsan 
upon  the  reaction,  it  must  be  admitted  that  the  results  obtained 
in  these  cases  demonstrate  beyond  all  question  the  superior 
specific  value  of  salvarsan  upon  treponema  pallidum. 

"Patients  who  have  been  previously  well  treated  with  mercury 
show  a  higher  percentage  of  negative  results  after  treatment  with 
salvarsan  than  those  who  have  received  no  mercurial  treatment. 
Thus  of  75  patients  who  had  received  mercurial  treatment  before, 
receiving  salvarsan,  84  per  cent  became  negative,  while  of  no 
patients  who  had  received  no  treatment  before  the  administra- 
tion of  salvarsan,  only  74.5  per  cent  became  negative. 

"In  order  to  illustrate  the  persistence  of  the  positive  Wasser- 


THE  WASSERMANN  REACTION 


III 


mann  reaction  after  treatment  with  mercurials,  another  table  has 
been  prepared  giving  the  method  of  treatment,  the  length  of  time 
the  patient  was  under  treatment,  the  number  of  cases  observed, 
and  the  intensity  of  the  reaction. 

Illustrating  the  Persistence  of  the  Wassermann  Reaction  after 
Treatment  with  Mercury  (after  Craig) 


Method  of 

Length  oj 
Treatment 

Number  of 
Cases 

Intensity  of  the  Reaction 

Treatment 

++ 

+ 

+- 

By  mouth 

I  month 

2 

2 

«        < 

2  months 

3 

I 

2 

((        I 

3       "' 

4 

2 

2 

«        i 

5       " 

6 

3 

3 

u            t 

6      " 

10 

7 

I 

2 

«           < 

7       " 

4 

3 

I 

i(          I 

8      " 

5 

4 

I 

ii          I 

9       " 

10 

7 

I 

2 

(C               I 

lO        " 

3 

2 

I 

u            t 

II       " 

3 

3 

11          < 

I  year 

24 

13 

6 

s 

<(            ( 

14  months 

2 

2 

li          < 

15       " 

2 

I 

I 

ii            i 

16       " 

4 

3 

I 

i(          I 

17       " 

I 

I 

it            i 

18      " 

7 

I 

4 

2 

il            i 

19      " 

4 

3 

I 

iC               i 

<£ 

20 

2 

I 

I 

CI               I 

2  years 

15 

8 

5 

2 

ii          I 

2.5      " 

3 

2 

I 

il          I 

3       " 

5 

I 

2 

2 

ii          i 

4       " 

I 

I 

By  mouth* 

7       " 

I 

I 

By  mouth* 

10       " 

I 

X 

By  mouth* 

12       " 

I 

I 

Inimctions 

2  months 

2 

2 

ii 

5      " 

I 

I 

ii 

6      " 

2 

2 

a 

I  year 

I 

^ 

*  Interrupted  treatment  during  this  time, 
hibition  of  hemolysis. 


-\ — h  indicates  complete  in- 


112  THE  TREATMENT  OF  SYPHILIS 

Mercury  not  a  Staple  Curative  Agent 

"The  table  illustrates  very  well  the  effect  of  treatment  with 
mercury  upon  the  Wassermann  reaction,  as  it  occurs  in  the  usual 
routine  of  serological  work  in  a  Wassermann  laboratory.  It 
shows  that  continued  treatment  with  the  drug  for  long  periods 
of  time  has  but  little  effect  upon  the  reaction  in  the  majority  of 
instances  and  that  interrupted  treatment  continued  for  many 
years  does  not  produce  a  negative  reaction  in  many  cases. 

"It  should  not  be  thought,  however,  from  the  data  given  here, 
that  the  Wassermann  reaction  never  becomes  negative  after 
treatment  with  mercury,  for  in  a  considerable  proportion  of 
cases  it  does,  and  the  writer  has  observed  many  cases  in  which  a 
negative  Wassermann  reaction  was  obtained  after  from  one  to 
two  years '  proper  treatment  with  this  drug,  but  it  has  been  his 
experience  that  most  cases  becoming  negative  after  mercurial 
treatment  relapse  in  the  course  of  months  or  a  year  or  two.  While 
he  would  not  go  so  far  as  to  state  that  the  Wassermann  test  never 
becomes  permanently  negative  after  treatment  with  mercury, 
it  has  been  his  experience  that  it  is  only  in  very  rare  instances  that 
a  permanently  negative  result  is  obtained  from  treatment  with  this 
drug  alone,  no  matter  how  it  is  administered  or  in  what  dosage. 

"In  fact,  it  has  been  proved  in  rabbits  experimentally  infected 
with  syphilis,  that  before  the  animals  can  be  rendered  sterile 
as  regards  treponema  pallidum  so  much  mercury  has  to  be  ad- 
ministered as  to  cause  either  the  death  of  the  animal  or  very 
serious  pathological  lesions  due  to  the  drug.  In  the  writer's 
rather  large  experience  he  has  never  personally  followed  a  case 
treated  with  mercury  alone,  in  which  the  Wassermann  test  was 
positive  before  treatment,  that  became  permanently  negative, 
although  many  cases  have  lost  the  positive  reaction  for  a  while 
but  have  invariably  become  positive  again  upon  the  cessation 
of  treatment.  However,  that  mercury  does  cure  syphilis  in  some 
instances,  is  proved  by  the  fact  that  individuals  are  encountered 
who  undoubtedly  had  the  disease  but  who  have  been  without 
symptoms  for  many  years  and  who  give  a  negative  Wassermann 
reaction  whenever  tested. 


THE  WASSERMANN  REACTION  1 13 

"If  the  patient's  blood  serum  be  carefully  titrated  after  the 
administration  of  either  salvarsan  or  mercury,  it  will  be  found 
that  in  almost  every  instance  the  Wassermann  reaction  is  in- 
fluenced to  some  extent,  although  it  may  never  become  negative. 
Thus,  many  cases  showing  a  two  plus  reaction,  or  absolute  in- 
hibition of  hemolysis,  with  quantities  of  blood  serum  as  small  as 
0.02  c.  c.  will  become  negative  for  this  amount  of  serum,  although 
giving  a  positive  reaction  with  the  usual  quantity  of  serum  used 
in  the  routine  tests;  i.  e.,  o.i  c.  c.  By  titrating  the  inhibitory 
strength  of  each  patient's  serum  it  will  be  found  that,  although 
the  Wassermann  test  may  apparently  be  uninfluenced  when  the 
diagnostic  amount  of  serum  is  used,  that  is,  o.i  c.  c,  some  diminu- 
tion in  the  strength  of  the  reaction  will  be  observed  in  amounts 
less  than  o.  i  c.  c.  In  using  the  Wassermann  test  as  a  control  of 
treatment  the  titration  of  the  patient's  serum  is  of  great  im- 
portance, as  will  be  noted. 

"Not  only  will  treatment  with  salvarsan  or  mercury  markedly 
influence  the  strength  of  the  reaction  but  if  treatment  is  com- 
menced early  in  the  primary  stage  of  the  disease  it  will  sometimes 
prevent  the  development  of  a  positive  reaction,  although  clinical 
symptoms  may  occur." 


CHAPTER  XII 

THE  TREATMENT  OF  SYPHILIS  OF  THE  CENTRAL  NERVOUS  SYSTEM 

It  is  unnecessary  in  a  book,  enabling  the  general  practitioner 
to  formulate  a  technic  for  the  ordinary  uses  of  salvarsan  and 
neosalvarsan,  to  discuss  in  elaborate  detail  the  treatment  of 
syphilis  of  the  central  nervous  system.  For  purposes  of  informa- 
tion, however,  the  method  of  utilizing  salvarsan  in  the  direct 
treatment  of  interstitial  and  parench3rmatous  lues  are  herein 
briefly  set  forth. 

Swift-Ellis  Method 

This  method  was  brought  to  the  attention  of  the  medical 
profession  by  Drs.  Homer  F.  Swift  and  Arthur  M.  W.  Ellis,  of 
New  York,  in  191 2  (N.  Y.  Med.  Jour.,  July  13,  191 2)  and,  with 
some  modifications,  is  still  in  use. 

The  original  technic  was  to  withdraw  the  blood  into  large  tubes 
by  means  of  a  MacRae  venous  puncture  needle,  after  intravenous 
injections  of  salvarsan  or  neosalvarsan,  to  separate  the  serum  and, 
on  the  following  day  to  dilute  it  to  40  per  cent  with  normal  saHne 
and  to  heat  it  at  56°  C.  for  thirty  minutes.  By  lumbar  puncture, 
15  c.  c.  of  spinal  fluid  was  withdrawn,  and  then  30  c.  c.  of  the 
diluted  serum  was  warmed  to  body  temperature  and  was  slowly 
injected  into  the  subarachnoid  space.  The  foot  of  the  bed  was 
raised  for  one-half  hour  after  treatment.  Drs.  Swift  and  ElKs 
found  that  there  might  be  a  slight  rise  in  temperature  after  the 
injection,  and  that  in  tabetics  there  were  often  hghtning  pains  in 
the  legs.  The  reaction  usually  passed  off  by  the  following  day 
and  the  patients  were  able  to  be  up  and  around  the  hospital. 

In  concluding  their  original  article,  they  observed  that  the 
best  results  could  probably  be  obtained  from  the  intravenous 
treatment  with  salvarsan  or  neosalvarsan,  combined  with  in- 


TREATMENT  OF  SYPHILIS  OF  CENTRAL  NERVOUS  SYSTEM  115 

traspinous  injections  of  the  patient's  own  serum,  possibly  with 
the  addition  of  small  amounts  of  neosalvarsan. 

Technic  of  Subarachnoid  Injections 

Drs.  Swift  and  Elhs  read  a  paper  before  the  Association  of 
American  Physicians,  May  7,  19 13,  in  which  they  set  forth  the 
following  technic  of  subarachnoid  injections  : 

"One  hour  after  the  intravenous  injection  of  salvarsan  40  c.  c. 
of  blood  is  withdrawn  directly  into  bottle-shaped  centrifuge 
tubes,  and  allowed  to  coagulate,  after  which  it  is  centrifugaHzed. 
The  following  day  12  c.  c.  of  serum  is  pipetted  off  and  diluted 
with  18  c.  c.  of  normal  sahne.  This  40  per  cent  serum  ^  is  then 
heated  at  56°  C.  for  one-half  hour.  After  lumbar  puncture  the 
cerebrospinal  fluid  is  withdrawn  until  the  pressure  is  reduced  to 
30  mm.  cerebrospinal  fluid  pressure.  The  barrel  of  a  20  c.  c. 
Luer  syringe  (which  has  a  capacity  of  about  30  c.  c.)  is  connected 
to  the  needle  by  means  of  a  rubber  tube  about  40  cm.  long.  The 
tubing  is  then  allowed  to  fill  with  cerebrospinal  fluid  so  that  no 
air  will  be  injected. 

"The  serum  is  then  poured  into  the  syringe  and  allowed  to 
flow  slowly  into  the  subarachnoid  space  by  means  of  gravity. 
At  times  it  is  necessary  to  insert  the  plunger  of  the  syringe  to 
inject  the  last  5  c.  c.  of  fluid.  It  is  important  that  the  larger  part 
of  the  serum  should  be  injected  by  gravity  and  if  the  rubber  tub- 
ing is  not  more  than  40  cm.  long  the  pressure  cannot  be  higher 
than  400  mm.  Usually  the  serum  flows  in  easily  under  even  a 
lower  pressure.  By  the  gravity  method  the  danger  of  suddenly 
increasing  the  intraspinous  pressure  to  the  danger  point,  such 
as  might  occur  with  rapid  injection  with  a  syringe,  is  avoided. 
Frequently  there  is  a  certain  amount  of  pain  in  the  legs,  com- 
mencing a  few  hours  after  the  injection.  The  pain  is  more  often 
noticed  in  tabetics  than  in  patients  with  cerebrospinal  s3/philis. 
It  can  usually  be  controlled  by  means  of  phenacetin  and  codein. 
Occasionally  morphin  is  required." 

1  In  patients  who  do  not  have  reactions  following  the  injection  of  40 
per  cent  serum,  the  strength  is  at  times  increased  to  50  or  60  per  cent,  or 
even  stronger. 


ii6  THE  TREATMENT  OF  SYPHILIS 

Continued  observation  demonstrated  to  their  satisfaction 
that  this  method  had  a  curative  action  on  the  syphilitic  process 
and  that,  where  especially  intensive  treatment  was  required,  as  in 
rapidly  advancing  tabes  or  paresis,  or  where  the  disease  had 
resisted  other  forms  of  treatment,  it  was  especially  indicated. 

Observations  on  Types  of  Response 

Dr.  Swift's  last  paper  read  before  the  College  of  Physicians, 
Philadelphia,  February  7,  191 7,  is  on  his  Observations  on  Types 
of  Response  in  the  Treatment  of  Syphilis  of  the  Central  Nervous 
System  (Amer.  Jour,  Syph.,  Vol.  i,  No.  3,  July,  191 7).  He 
classifies  the  various  types  under  the  following  main  headings : 

1.  Vascular. — The  essential  lesion  is  an  endarteritis,  and  the 
nervous  lesion  is  due  to  disturbed  circulation. 

2.  Exudative. — The  most  marked  lesion  is  cellular  thickening 
of  the  supporting  membranes  or  perivascular  spaces,  with  gumma 
formation  and  subsequent  mechanical  injury  to  cortex,  tracts, 
and  intradural  portions  of  nerves. 

3.  Parenchymatous. — The  striking  picture  is  tract  or  cortical 
degeneration,  but  in  which  the  essential  lesion  is  probably  a 
chronic  meningitis  and  perivasculitis.  At  least  this  appears  to 
be  true  of  the  various  tabetic  manifestations.  In  paresis  a  true 
inflammation  of  the  cortex  seems  to  exist.  This  peculiarity  in 
the  paretic  process  probably  explains  the  intractability  of  this 
condition  to  treatment. 

The  various  factors  considered  in  classifying  the  cases  have 
been  found  by  Dr.  Swift  to  be:  time  since  infection;  the  clinical 
picture;  the  laboratory  findings;  and  the  response  to  treatment. 
He  recognizes  these  groups : 

I.  Early  Meningitis. 

(a)  Cases  which  respond  readily  to  the  general  administration 
of  salvarsan  and  mercury. 

(b)  Cases  which  respond  more  slowly  to  salvarsan  intra- 
venously, and  tend  to  relapse  when  salvarsan  is  discontinued,  or 
mercury  is  substituted. 


TREATMENT  OF  SYPHILIS  OF  CENTRAL  NERVOUS  SYSTEM  117 

(c)  Cases  which  do  not  clear  up  under  most  intensive  general 
treatment,  but  which  respond  satisfactorily  to  intraspinal  treat- 
ment. 

2.  Later  Forms  of  Central  Nervous  Syphilis  of  the  Exudative 
Type. 

The  abnormal  elements  in  the  cerebrospinal  fluid  usually 
disappear  rapidly  under  general  administration  of  iodides,  mer- 
cury and  salvarsan. 

3.  Tabes  Dorsalis. 

(a)  Cases  which  show  a  rapid  response  to  general  treatment. 

(b)  Cases  which  show  no  improvement  or  very  slow  improve- 
ment under  general  treatment. 

(c)  Cases  which  show  a  satisfactory  response  to  intraspinal 
treatment  alone. 

(d)  Cases  which  have  responded  slowly  to  general  treatment, 
but  which  respond  more  rapidly  when  intraspinal  injections  of 
"autosalvarsanized  serum"  are  given. 

(e)  Cases  which  relapse  when  treatment  is  discontinued. 

(f)  Cases  which  continue  to  improve  when  treatment  is  dis- 
continued. 

4.  Paralytica  Dementia. 

(a)  Cases  with  marked  improvement  in  both  clinical  signs  and 
the  condition  of  the  cerebrospinal  fluid. 

(b)  Cases  with  marked  clinical  improvement  but  no  change 
in  the  cerebrospinal  fluid. 

(c)  Cases  with  progressive  downward  clinical  course  and 
stationary  condition  of  the  cerebrospinal  fluid. 

5.  Patients  Clinically  not  Paralytica  Dementia  in  whom  the 
Cerebro-spinal  Fluid  shows  a  Paretic  Type  of  Gold  Curve. 

(a)  Cases  which  respond  rapidly  to  combined  intravenous  and 
intraspinal  treatment. 

(b)  Cases  which  respond  more  slowly  and  show  a  decided 
tendency  for  the  abnormal  elements  to  recur  when  treatment  is 
discontinued. 


Il8  THE  TREATMENT  OF  SYPHILIS 

Summarized  Conclusions 

The  conclusions  reached,  following  a  very  comprehensive 
study  of  the  conditions,  are: 

"Before  undertaking  the  treatment  of  a  patient  with  any  form 
of  cerebrospinal  syphilis,  it  is  important  to  determine  what 
symptoms  are  due  to  inflammation  or  exudation  and  what  are 
due  to  degeneration  of  tracts  or  cortex.  It  is  also  advisable  to 
determine  the  intensity  of  the  irritative  condition  as  indicated  by 
the  cerebrospinal  fluid.  In  general  the  lesions  due  to  inflamma- 
tion or  exudation  are  much  improved  or  eliminated  by  the 
general  treatment  of  the  patient.  Those  due  to  degeneration 
are  little,  if  any,  affected. 

"Treatment  should  be  directed  not  only  towards  the  elimina- 
tion of  symptoms,  but  towards  the  elimination  of  the  underlying 
process,  namely,  S3^hilis.  In  most  patients  with  early  meningitis 
and  in  those  with  what  was  formerly  termed  tertiary  syphiUs 
of  the  central  nervous  system,  the  symptoms  due  to  exudation 
respond  in  a  satisfactory  manner  to  the  general  administration  of 
salvarsan,  mercury,  and  potassium  iodid. 

"Occasionally,  a  case  is  met  in  which  intraspinal  treatment 
seems  to  be  necessary  in  order  to  eradicate  completely  the  cen- 
tral nervous  lesions.  Likewise  in  tabes  dorsahs,  many  cases 
respond  satisfactorily  to  the  general  administration  of  salvarsan 
and  mercury.  On  the  other  hand,  in  a  considerable  number  of 
tabetics,  the  addition  of  intraspinal  injections  of  senun  to  in- 
travenous treatment  with  salvarsan  seems  to  hasten  the  ehmina- 
tion  of  abnormal  elements  in  the  cerebrospinal  fluid  and  leads 
to  a  permanent  arrest  of  the  degeneration. 

"It  is  advisable  to  continue  the  treatment  of  patients  suffering 
from  cerebrospinal  syphihs  or  tabes  dorsahs  until  the  cerebro- 
spinal fluid  is  normal  and  remains  so.  A  possible  exception  may 
be  made  in  reference  to  excess  globulin,  for  an  increased  globuhn 
is  not  infrequently  found  years  after  all  other  abnormal  elements 
have  disappeared  from  the  fluid. 

"In  paralytica  dementia,  while  much  benefit  may  be  expected 
in  increasing  the  number  and  length  of  remissions,  the  ultimate 


TREATMENT  OF  SYPHILIS  OF  CENTRAL  NERVOUS  SYSTEM  119 

hope  for  recovery  is  slight.  When  a  paretic  type  of  gold  curve  is 
found  in  the  fluid  of  patients  in  whom  the  clinical  diagnosis  of 
paresis  is  not  justified,  the  most  intensive  form  of  treatment 
should  be  instituted  from  the  beginning.  It  is  probable  that  the 
finding  of  this  paretic  type  of  gold  curve  often  helps  us  to  make  a 
diagnosis  of  paresis  before  clinical  symptoms  of  the  disease  are 
present.  This  early  diagnosis  with  consequent  early  treatment 
may  be  of  extreme  importance  in  preventing  the  development  of 
the  outspoken  condition. 

"Finally,  treatment  must  be  individualized,  given  in  courses, 
and  the  condition  of  the  fluid  determined  at  the  end  of  each 
course  and  at  the  beginning  of  the  subsequent  course.  In  this 
way,  the  indication  for  kind  of  treatment,  as  well  as  the  manner 
of  response,  is  much  more  certainly  determined  than  if  we  de- 
pend on  cKnical  symptoms  and  objective  findings  alone." 

Dr.  Ogilvie's  Modification 

Dr.  Hanson  S.  Ogilvie  of  New  York,  believes  it  necessary  to 
ehminate  the  uncertain  salvarsan  content  of  the  Swift-EUis 
serum  by  preparing  in  vitro  a  senun  of  definitely  known  thera- 
peutic value.  His  technic  is  as  follows  (Amer.  Jour.  Syph., 
Vol.  I,  No.  3,  July,  191 7): 

"Ten  cubic  centimeters  of  clear  human  serum  are  obtained 
either  by  centrifuging  a  tube  of  freshly  drawn  blood  at  approxi- 
mately 3000  revolutions  for  from  ten  to  fifteen  minutes,  or  per- 
mitting a  clot  to  form  by  letting  it  stand  overnight.  (Originally 
15  c.  c.  was  recommended,  but  it  has  since  been  found  that  the 
smaller  amount  is  sufficient,  and  productive  of  equally  as  good 
results.)  It  is  not  essential  that  an  autogenous  serum  be  em- 
ployed. 

"Sera  taken  indiscriminately  from  patients  can  be  used,  and 
where  a  large  number  of  patients  are  to  be  treated  the  sera  can 
be  pooled  and  divided  into  amounts  of  10  c.  c.  each.  Care  should 
be  taken  to  free  the  serum  absolutely  from  fibrin  and  ceUular 
elements,  and  to  this  end  it  is  sometimes  necessary  to  centrifuge  a 
second  time.  Under  no  circumstances  should  a  serum  be  used 
that  contains  hemolized  red  blood  ceUs.    The  test  tube  containing 


I20  THE  TREATMENT  OF  SYPHILIS 

the  serum  is  then  placed  in  a  water  bath  at  body  temperature 
until  the  salvarsan  is  ready  to  be  added. 

"/w  preparing  the  salvarsan  solution  the  greatest  care  must  be 
exercised  in  alkalinizing  it.  The  sodium  hydroxid  solution  must 
be  fresh  (preferably  not  more  than  four  or  five  days  old),  and 
only  a  suj6S.cient  amount  added  to  very  faintly  alkaUnize  the  sal- 
varsan solution.  The  salvarsan  solution  will  be  more  readily 
and  accurately  alkalinized  if  the  sodium  hydroxid  is  added  while 
the  former  is  about  body  temperature. 

"A  very  hot  salvarsan  solution  requires  more  sodium  hydroxid 
to  faintly  alkalinize  it,  but  when  it  is  cooled  down  the  degree  of 
alkaUnity  is  apparently  markedly  increased,  and  a  serum  charged 
with  such  a  solution  invariably  produces  a  reaction  (usually  root 
pain)  when  given  intraspinally.  The  salvarsan  solution  should 
be  prepared  so  that  each  cubic  centimeter  contains  one  milHgram 
of  the  drug.  While  at  first  thought  of  minor  importance,  this 
part  of  the  technic  should  be  carefully  considered. 

"Unless  one  is  familiar  with  laboratory  work  to  some  extent 
he  is  liable  to  miscalculate  his  dilution  strengths  and  give  more 
of  the  drug  than  is  intended.  With  a  i  c.  c.  pipette,  graduated 
into  tenths  or  twentieths,  the  exact  amount  of  salvarsan  desired 
for  the  case  under  treatment  is  added  to  the  ten  cubic  centimeters 
of  serum,  care  being  taken  that  the  two  solutions  are  at  the  same 
temperature  (preferably  37.5°  C).  The  serum  should  then  be 
gently  agitated  to  insure  thorough  mixing.  It  is  now  placed  in  a 
water  bath  thermostat  at  37.5°  C.  for  forty-five  minutes.  From 
this  it  is  placed  in  a  thermostat  at  56.0°  C.  for  thirty  minutes, 
after  which  it  is  removed  from  the  water  bath  and  as  soon  as  the 
temperature  is  reduced  to  approximately  that  of  the  body,  it  is 
ready  to  be  given  to  the  patient." 

Suggestions  in  Intraspinal  Treatment 

No  changes  have  been  made  in  this  techm'c  since  1917.  Dr. 
Ogilvie  insists  that  the  serum  should  be  given  not  later  than 
three  hours  after  it  is  removed  from  the  last  thermostat,  and  that 
the  treatment  is  better  borne  if  it  be  given  within  an  hour  of  its 
preparation. 


TREATMENT  OF  SYPHILIS  OF  CENTRAL  NERVOUS  SYSTEM  121 

He  also  states  that  salvarsan  and  not  neosalvarsan  should  be 
employed  for  intraspinal  injection. 

In  paresis  Dr.  Ogilvie  employs  a  relatively  stronger  serum  than 
in  other  types  of  neurologic  syphilis,  but  he  states  that  the  max- 
imum amount  of  salvarsan  that  can  be  given  with  safety  is  one- 
half  of  a  milligram,  and  that  treatments  with  this  strength  should 
rarely  be  repeated  oftener  than  every  two  weeks. 

He  decries  making  a  lumbar  puncture  with  the  patient  sitting 
up,  and  he  warns  that  after  the  treatment  the  patient  should  be 
kept  on  his  back  without  pillows  for  from  five  to  six  hours  and 
in  a  recumbent  position  for  from  thirty-six  to  forty-eight  hours. 

He  lays  particular  emphasis  on  the  fact  that  while  intraspinal 
treatment  is  of  the  greatest  value  in  certain  types,  such  as  the 
interstitial  (formerly  referred  to  as  the  cerebrospinal),  it  can 
accomplish  little  more  than  the  intravenous  in  others,  such  as 
the  parenchymatous;  and,  furthermore,  that  not  every  case  of 
interstitial  syphilis  of  the  central  nervous  system,  where  the  cord 
or  the  cerebrum  is  involved,  requires  intraspinal  treatment.  A 
relatively  smaU  percentage  of  cases  apparently  respond  quite  as 
well  to  intravenous  treatment  with  mercury  intramuscularly. 

Dr.  Ogilvie  is  further  of  the  opinion  that  physicians  generally 
have  the  impression  that  every  one  of  these  cases  should  be 
treated  intraspinally,  but  he  says  that  a  careful  study  of  the 
cerebrospinal  fluid  findings  and  the  clinical  picture  presented 
should  decide  which  course  is  the  proper  one  to  pursue. 

A  Persistent  Positive  Means  a  Spirochetal  Focus 

The  physician  has  to  bear  in  mind  that  a  persistent  positive 
Wassermann  always  indicates  a  spirochetal  focus  in  the  body. 
These  may  be  in  a  quasi-harmless  symbiosis  in  an  unimportant 
tissue  of  the  body  and,  consequently,  it  is  imnecessary  to  subject 
the  patient  to  continuous  courses  of  treatment.  On  the  other 
hand,  however,  the  offending  focus  may  be  in  the  nervous  or  the 
vascular  systems  and,  therefore,  a  very  thorough  examination  is 
demanded.  The  lumbar  puncture  and  the  cytologic  examination 
of  the  cerebrospinal  fluid,  and  use  of  the  globulin  test  and  the 
colloidal  gold  test  and  every  other  diagnostic  test  are  absolutely 


122  THE  TREATMENT  OF  SYPHILIS 

demanded.  Syphilologists  agree  that  even  in  the  absence  of 
signs  pointing  directly  to  invasion  of  the  ner/ous  system  in  the 
face  of  a  Wassermann  which  continues  persistently  positive,  the 
physician  is  justified  in  domg  a  lumbar  puncture. 


Importance  of  Intraspinal  Treatment 

Dr.  John  A.  Fordyce  of  Columbia  University,  the  leading 
authority  on  syphilis  in  the  United  States,  in  a  paper  entitled 
"Intra-spinal  Therapy  in  Neurosyphilis"  (Am.  Jour.  SypM., 
Vol.  m.  No.  2,  July,  1 919)  says  that  until  conclusion  by  cHni- 
cal  study,  serology  and  autopsy  findings  leads  to  the  behef  that 
foci  are  estabHshed  in  the  various  tissues,  it  may  require  years  to 
modify  or  destroy  functional  capacity.  He  beheves  that  a  com- 
plete cure  is  the  exception  rather  than  the  rule  unless  treatment 
is  begun  in  the  early  months  of  the  infection.  An  aortitis  or 
aortic  insufficiency  is  not  the  result  of  a  sudden  invasion  by 
spirochetes  many  years  after  the  primary  sore,  but  the  effect 
of  a  slow  tissue  reaction  due  to  the  implantation  of  the  organisms 
in  the  florid  stage  of  the  disease.  In  the  central  nervous  system 
the  spirochetal  attacks  may  cause  marked  subjective  or  objective 
symptoms  and  signs  Hke  headache,  dehrium  or  paralysis.  On 
the  other  hand,  an  individual  so  infected  may  remain  free  from 
all  symptoms  for  years  until  some  important  center  or  tract  is 
compromised. 

Dr.  Fordyce  believes  that  the  spirochete  may  be  deposited  in 
the  cerebral  cortex  during  the  period  of  generalization  of  the 
organisms,  and  remain  hidden  away  in  the  deeper  parts  of  the 
brain  and,  only  in  after  years,  will  they  produce  a  disturbance  of 
function.  In  certain  cases  they  may  temporarily  stimulate  the 
intellectual  powers  and  lead  to  achievements  of  more  than 
normal  briUiancy. 

The  progress  of  the  infection  in  the  central  nervous  system 
may  be  modified  or  delayed  by  therapeutic  agents,  but  it  is 
seldom  cured.  The  modified  or  delayed  mfection  is  latent  for  a 
time  and  then  relapses.  This  condition  may  continue  for  years 
before  it  finally  terminates  in  irreparable  damage. 


TREATMENT  OF  SYPHILIS  OF  CENTRAL  NERVOUS  SYSTEM  123 

Necessity  of  Locating  the  Focus  of  Infection 

Dr.  Fordyce  emphasizes  the  necessity  of  locating  the  focus  of 
infection  and  his  statistics  show  that  a  larger  percentage  of 
deaths  are  due  to  cardiovascular  disease  of  syphihtic  origin  than 
to  any  other  phase  of  the  disease.  Therefore,  when  a  persistent 
positive  serum  reaction  is  present,  he  advises  a  careful  exami- 
nation of  the  heart  and  aorta. 

A  positive  Wassermann  reaction  which  remains  uninfluenced  by 
intensive  treatment  for  years,  or  which  returns  after  a  discon- 
tinuance of  treatment,  is  often  caused  by  neurosyphilis  without 
any  or  with  very  few  objective  signs.  The  blood  reaction  may 
become  negative  after  treatment  but  it  will  be  re-infected  by 
the  spinal  fluid.    Dr.  Fordyce  lays  especial  emphasis  on  this  fact. 

During  the  past  five  years  he  has  had  a  very  large  experience 
with  intraspinal  treatment,  and  he  finds  that  a  serum  properly 
prepared  and  diluted  with  from  30  to  40  c.  c.  of  spinal  fluid  be- 
fore introduction  into  the  spinal  canal  may  be  employed  without 
danger  in  a  vast  majority  of  patients  in  whom  indications  are 
present  for  its  use. 

The  Fordyce  Technic 

"The  patient  is  given  an  intravenous  injection  of  salvarsan  and 
approximately  one-half  hour  later  50  c.  c.  of  blood  are  withdrawn 
from  an  arm  vein.  This  is  permitted  to  clot  over  night  in  the  re- 
frigerator. The  next  morning  it  is  centrifugalized  and  the  serum 
pipetted  into  a  sterile  tube.  After  a  second  centrifugaKzation 
to  insure  removal  of  all  red  blood  cells  the  clear  serum  is  pipetted 
into  another  tube.  To  this  is  added  the  desired  amount  of  sal- 
varsan, namely:  from  7io  to  ]4,  V3  or  in  certain  cases  of  paresis 
^  mg.  This  mixture  is  then  inactivated  at  55  to  57°  C.  for  }4 
hour. 

"To  arrive  at  the  proper  dosage  for  intraspinal  therapy  we 
make  a  dilution  of  salvarsan  of  which  30  c.  c.  represents  o.i  gram 
of  the  drug;  10  c.  c.  is  then  further  diluted  with  0.5  per  cent 
saline  solution  to  35  c.  c.  of  which  i  c.  c.  equals  i  mg.  of  salvarsan. 
In  the  administration  of  the  medicated  sermn  a  lumbar  puncture 


124  THE  TREATMENT  OF  SYPHILIS 

is  made  and  about  lo  to  20  c.  c.  of  fluid  withdrawn.  A  small 
gravity  tube  with  a  capacity  of  about  40  c.  c.  is  then  attached 
to  the  needle  and  the  fluid  allowed  to  flow  in  until  it  holds  about 
30  c.  c.  To  this  is  slowly  added  the  serum  and  the  mixture  is 
permitted  to  flow  back  into  the  canal." 

Types  which  call  for  Intraspinal  Treatment 

Dr.  Fordyce  makes  his  position  clear  regarding  the  indications 
for  intraspinal  therapy  in  that  he  beHeves  the  method  in  ques- 
tion is  of  value  "in  certain  types  of  neurosyphihs  which  fail  to 
respond  to  treatment  by  other  channels  and  in  which  the  spinal 
fluid  reveals  an  active  syphiHtic  lesion.  If  a  patient  after  in- 
tensive treatment  with  arsphenamine,  mercury  and  potassiimi 
iodid  shows  Uttle  or  no  improvement  in  his  symptoms,  blood  or 
fluid  reactions,  some  other  method  of  therapeutic  attack  would 
be  clearly  indicated." 

He  finds  that  intraspinal  treatment  has  been  followed  by  per- 
sistent negative  phases  and  chnical  improvement  or  cure  and,  he 
is  therefore,  much  more  convinced  of  its  value.  Since  adding 
salvarsanized  serum  to  30  or  40  c.  c.  of  withdrawn  fluid  and  per- 
mitting the  mixture  to  slowly  return  by  gravity  his  results  have 
been  more  rapid  and  striking. 

Dr.  Fordyce  has  a  Hst  of  seventy-five  cases  of  various  neuro- 
syphilitic  t3^es  in  which  the  findings  are  negative  and  many 
of  them  have  been  persistently  so  for  periods  of  from  one  to  three 
years.  He  observes  that  activation  of  latent  foci  or  lesions  in  the 
central  nervous  system  may  follow  the  administration  of  mercury 
or  salvarsan  and  cause  an  acute  encephalitis  and  death.  These 
so-called  Herxheimer  reactions  as  a  rule  subside  and  are  followed 
frequently  by  clinical  improvement.  It  is  not  always  possible 
to  foresee  them  but  they  can  usually  be  prevented  by  a  careful 
preliminary  use  of  mercury  and  salvarsan  in  moderate  doses 
before  the  use  of  salvarsanized  senun  intraspinally. 

Intraspinal  Treatment  in  Preserving  Vision 

Emphasizing  the  necessity  of  systematic  eye  examinations  in 
all  cases  of  lues.  Dr.  Fordyce  expresses  the  opinion  that  every 


TREATMENT  OF  SYPHILIS  OF  CENTRAL  NERVOUS  SYSTEM  125 

case  of  optic  atrophy,  whether  primary  or  part  of  a  tabetic  or 
paretic  syndrome,  demands  an  examination  of  the  spinal  fluid 

at  the  earliest  possible  moment.  In  case  the  spinal  fluid  shov/s 
primary  or  associated  meningitis,  with  other  positive  phases  of 
syphiKs,  a  method  of  treatment  should  be  begun  which  offers 
hope  of  arresting  the  destructive  process.  His  experience  is  that 
but  little  can  be  expected  from  mercury,  potassium  iodid  or  sal- 
varsan  intravenously,  and  he  beUeves  that  intraspinal  treatment 
is  indicated  in  optic  atrophy  where  the  fluid  shows  a  meningitis 
with  the  positive  phases  of  s3^hiHs. 

Persistent  intraspinal  treatment  when  indicated  by  the  fluid 
findings  can  arrest  the  progress  of  many  cases  and  preserve  the 
remaining  vision.  Salvarsanized  serum  directly  introduced  into 
the  lumbar  subarachnoid  space  diffuses  itself  more  slowly  and 
accomplishes  less  than  when  diluted  outside  the  body  with  a  large 
quantity  of  fluid. 

Dr.  Fordyce  feels  that  too  little  time  has  elapsed  since  begin- 
ning the  examination  of  the  spinal  fluid  in  secondary  syphilis  to 
enable  him  to  speak  with  certainty  as  to  the  type  of  early  neuro- 
syphihs  which  may  develop  paresis.  He  has,  however,  spinal 
fluid  tests  which  indicate  the  probable  site  of  the  syphiHtic  in- 
fection of  the  central  nervous  system  and  a  large  number  showing 
to  what  degree  these  reactions  resist  therapeutic  attacks  which 
influence  the  more  superficial  types  of  neurosyphilis.  He  regards 
as  of  favorable  prognostic  import  a  spinal  fluid  which  shows  a 
positive  Wassermann  reaction  in  the  lower  dilutions  with  a 
luetic  gold  sol  curve,  that  is  so  far  as  regards  the  positive  develop- 
ment of  paresis.  A  persistent  reaction  in  the  high  dilutions, 
however,  with  a  paretic  curve  is  of  graver  significance.  When 
Httle  or  no  impression  can  be  made  on  the  Wassermann  in  the 
spinal  fluid  by  persistent  intraspinal  treatment,  the  probable 
development  of  paresis  must  always  be  kept  in  mind. 

Encouraging  Results  in  Pre-paresis 

He  observes  that  the  results  obtained  by  the  intraspinal  treat- 
ment in  pre-paresis  when  sufficiently  prolonged  at  times  are  so 
encouraging  that  he  feels  justified  in  carrying  it  out  to  the  Hmit 


126  THE  TREATMENT  OF  SYPHILIS 

of  the  patient's  endurance.  He  believes  that  with  the  careful 
technic  now  employed  and  with  the  proper  preparatory  treatment 
danger  to  the  patient's  life  or  possible  damage  to  the  cord  or 
brain  has  been  entirely  eliminated.  He  remarks  in  this  connec- 
tion that  such  treatment  by  the  inexperienced  without  labora- 
tory faciUties  and  proper  serological  control  will  certainly  fail. 

Summary  of  Dr.  Fordyce's  Conclusions 

"Results  following  the  treatment  of  S5^hihs  are  largely  de- 
pendent on  the  age  of  the  infection.  For  this  reason  the  impor- 
tance of  early  diagnosis  and  energetic  treatment  have  been  em- 
phasized. 

"In  early  syphilis  the  spirochetes  are  numerous,  widely  dis- 
seminated and  cause  little  or  no  tissue  destruction,  organisms 
accessible  to  the  specific  drugs  are  destroyed  and  in  favorable 
cases  cures  are  obtained.  In  a  large  percentage  of  cases,  however, 
the  treatment  is  not  carried  out  in  an  intensive  fashion  and  as  a 
result  the  organisms  persist  in  the  viscera,  cardio-vascular  or 
nervous  system  and  slowly  cause  tissue  reactions  and  final  de- 
generation. 

"A  serological  cure  in  cases  of  S3^hilis  in  the  late  secondary 
stage  and  following  this  is  difficult  to  obtain  and  requires  ex- 
pert knowledge  in  the  use  of  our  therapeutic  agents. 

"When  the  central  nervous  system  is  invaded  the  problem  is 
complicated  by  the  highly  organized  nature  of  the  tissues,  the 
results  of  secondary  degenerations  and  the  inaccessibility  of  the 
spirochete  in  certain  types  of  neurosyphilis.  In  the  majority  of 
cases  a  strain  of  spirochete  invades  the  cerebrospinal  axis  before 
or  during  the  treatment  by  drugs  by  the  usual  channels  and  fails 
to  respond  to  continuous  administration  of  antisphilitic  agents 
given  in  this  way.  The  progress  of  the  infection  may  be  delayed 
by  drugs  assisted  by  the  defensive  forces  of  the  body.  It  is 
seldom  cured.  Clinical  symptoms  are  modified  or  disappear  for  a 
time  but  usually  return  unless  the  serology  of  the  spinal  fluid  and 
blood  becomes  negative  for  a  definite  period. 

"The  control  of  the  pathological  changes  in  the  brain  and  cord 


TREATMENT  OF  SYPHILIS  OF  CENTRAL  NERVOUS  SYSTEM  127 

is  only  possible  by  repeated  examinations  of  the  spinal  fluid.  We 
have  no  definite  data  as  to  the  number  of  cases  of  neuros3^hiIis 
cured  by  the  older  methods  of  treatment.  Frequent  relapses  and 
eventual  termination  in  degenerations  of  the  majority  of  cases 
so  treated  lead  to  the  behef  that  few  were  cured.  The  need, 
therefore,  is  for  a  more  direct  method  of  attacking  spirochete  in 
the  central  nervous  system. 

Intensive  Treatment  Indicated 

"  The  intensive  use  of  salvarsan  intravenously  combined  with 
mercury  and  potassium  iodid  cures  a  definite  number  of  cases. 
All  methods  of  treatment  fail  in  certain  types  of  neurosyphilis 
because  of  the  inability  to  reach  the  organisms  in  inaccessible 
localities  and  because  of  secondary  degenerations  of  tissue  which 
cannot  be  restored.  Intra-spinal  treatment  is  successful  in  cer- 
tain types  which  fail  to  respond  to  other  methods  or  which  be- 
come stationary  after  a  definite  clinical  and  serological  improve- 
ment. 

"Success  or  failure  in  the  use  of  intraspinal  therapy  depends 
on  the  technic  employed  and  the  persistence  of  the  physician  in 
carrying  it  out.  Above  all  it  depends  on  the  cyto-biological  in- 
dications which  are  present  in  the  spinal  fluid  for  initiating  or 
persisting  in  this  mode  of  therapy. 

"The  cytology  is  usually  the  first  phase  to  be  influenced  in 
persistent  infections.  In  some  cases  treatment  must  be  continued 
for  from  one  to  two  years  before  a  definite  impression  is  made  on 
the  globuHn  content  or  the  Wassermann  reaction.  Modification 
in  the  intensity  of  the  globulin  reaction  is  usually  followed  by  a 
weakening  in  the  strength  of  the  Wassermann  and  by  a  change  in 
the  gold  sol  reaction.  Rapid  changes  in  the  Wassermann  reaction 
where  strongly  positive  in  the  high  dilutions,  in  my  experience, 
do  not  occur  except  in  cases  of  early  syphilitic  meningitis.  In 
old  cases  of  neurosyphilis  a  gradual  diminution  in  the  intensity 
of  the  Wassermann  reaction  is  of  good  prognostic  import  and, 
when  it  finally  becomes  negative,  cases  I  have  examined  after 
one,  two  and  three  years  have  shown  no  return  of  any  of  the 
previous  phases." 


128  THE  TREATMENT  OF  SYPHILIS 

Intravenous  rather  than  Intraspinal  Medication 

Another  school  favors  the  treatment  of  syphiKs  of  the  nervous 
system  by  intensive  intravenous  rather  than  intraspinal  medica- 
tion. Dr.  Bernard  Sachs  of  Mt.  Sinai  Hospital,  New  York,  is 
the  leader  of  this  school.  He  believes  that  by  the  intravenous 
method  no  lives  are  lost,  no  unnecessary  paralyses  result  from 
treatment  and  far  less  harm  will  be  done  than  if  the  intra- 
spinal method  were  generally  adopted.  He  points  out  (Arch. 
Neur.  and  Psych.,  Vol.  i,  pp.  277-284,  March,  191 9)  that  the 
early  and  persistent  use  of  arsphenamine  intravenously  ad- 
ministered makes  the  entire  course  of  the  disease  far  less  pro- 
gressive than  formerly.  He  thinks  it  no  exaggeration  to  state 
that  in  innumerable  cases  he  has  been  able  to  check  the  progress 
of  the  disease.  He  says  "there  is  a  vast  difference  between  the 
acute  infectious  disorders  and  the  more  chronic  syphilitic  disease 
dependent  on  the  difference  in  the  manner  of  invasion  in  the 
toxic  products  formed  and  in  the  final  habitat  of  the  respective 
micro-organisms. 

"In  general  paresis  and  in  tabes  the  chief  lesions  are  within  the 
substance  of  the  brain  or  of  the  cord  far  removed  from  actual 
contact  with  the  cerebrospinal  fluid.  It  is  for  that  reason  almost 
impossible  to  bring  the  spirocheticidal  remedy  into  immediate 
contact  with  the  foci  of  disease  unless  these  remedies  can  be  in- 
troduced through  the  blood  streams.  It  is  only  in  the  earh'est 
stages  of  tabes  dorsahs  that  the  disease,  as  we  have  long  since 
known,  involves  the  meninges  and  the  spinal  gangha;  later  on  it 
sets  up  marked  degenerative  changes  in  the  spinal  tissue,  and 
these  secondary  changes  are  entirely  beyond  the  reach  of  the 
cerebrospinal  fluid  and  its  contents.  In  the  remaining  meningo- 
encephahtic  and  meningo-myehtic  processes  of  specific  origin, 
more  or  less  exudative  in  character,  we  would  suppose  that  spiro- 
cheticidal substances  introduced  in  the  cerebrospinal  fluid  might 
have  an  active  therapeutic  effect  if  such  substances  could  course 
freely  in  the  cerebrospinal  fluid  and  if  it  could  be  shown  that  they 
were  retained  in  this  fluid  for  any  satisfactory  period  of  time. 

"Four  years  ago,  with  the  assistance  of  Professor  Benedict, 


TREATMENT  OF  SYPHILIS  OF  CENTRAL  NERVOUS  SYSTEM  129 

we  succeeded  in  showing  that  salvarsan  introduced  in  the  usual 
quantities  into  the  blood  current  appeared  in  the  cerebrospinal 
fluid  in  appreciable  quantities.  In  this  way  we  refuted  the  doc- 
trine of  the  impermeability  of  the  choroid  plexus  and  that  sal- 
varsan introduced  intravenously  could  not  be  expected  to  exert 
any  influence  over  the  cerebral  and  spinal  tissues.  The  question, 
therefore,  narrowed  itself  practically  to  this:  Whether  or  not  as 
much  spirocheticidal  substances — for  example,  arsphenamine — 
reached  the  cerebrospinal  canal  in  intravenous  treatment,  as  it 
was  safe  to  introduce  directly  into  the  cerebrospinal  fluid  by 
lumba  puncture." 

A  Direct  Versus  a  Round-about  Route 

Dr.  Sachs  sets  forth  the  fact  that  when  a  metalUc  substance, 
like  arsphenamine,  is  introduced  into  the  spinal  canal  it  is  rapidly 
absorbed  into  the  venous  system  and  asks,  if  this  be  true,  "why 
not  use  the  venous  system  at  once  for  the  conveyance  of  this 
metallic  substance  rather  than  the  round-about  route  via  the 
cerebrospinal  canal." 

He  also  shows  that  British  authors,  among  them  Halliburton, 
have  abandoned  the  use  of  arsphenamine  in  locomotor  ataxia 
and  other  late  syphilitic  affections  through  the  cerebrospinal 
fluid,  because  they  claim  it  is  fatal  both  to  the  syphiHtic  organism 
and  to  the  patient. 

In  his  own  service  at  Mt.  Sinai,  Dr.  Sachs  observes  that  he  has 
obtained  the  most  satisfactory  results  "from  intravenous  injec- 
tions administered  on  alternate  days  for  a  period  of  three  to 
four  weeks  according  to  the  s3miptoms  presented  by  the  patient, 
and  then  allowing  a  period  of  complete  rest  or  giving  weekly 
or  semi-weekly  injections  of  saHcylate  of  mercury  for  a  period 
of  four  to  six  weeks  and  then  again  starting  in  with  the  same 
course  of  arsphenamine  injections.  Some  of  the  patients  have 
received  as  many  as  forty  or  fifty  intravenous  injections  within  a 
period  of  a  year  or  eighteen  months.  There  may  be  a  few  men 
who  could  with  impunity  give  the  same  number  of  intraspinal 
injections,  but  the  patient  wiU  certainly  be  none  the  better  for 


130  THE  TREATMENT  OF  SYPHILIS 

them  and  even  the  most  skillful  of  the  intraspinal  injectionists 
have  had  disagreeable  experience  to  record." 

Intravenous  Method  Unsurpassed 

Dr.  Sachs  is  emphatic  in  his  statement  that  no  other  specific 
medication  has  ever  been  as  satisfactory  as  the  intravenous  use 
of  arsphenamine.  Where  there  is  good  reason  to  suspect  that 
the  symptoms  of  nervous  diseases  are  due  to  the  specific  poison, 
the  antisyphih'tic  medication  should  be  begun  as  early  as  possible 
and  persisted  in  as  long  as  possible. 

"In  the  cases  of  intense  headaches,  probably  meningeal,  in 
some  of  the  earliest  forms  of  specific  optic  neuritis,  in  the  large 
number  of  cases  of  cerebrospinal  syphilis  with  actual  nerve  palsies 
with  moderate  paralytic  symptoms,  with  incomplete  vesical 
disturbance;  in  the  victims  of  vascular  disease,  in  arteritis  luet- 
ica,  and  above  all,  in  a  rather  important  group  of  syphihtic 
epilepsies,  intensive  intravenous  treatment  leads  not  infrequently 
to  a  cure  and  very  often  to  a  marked  improvement  in  all  the 
symptoms.  But  in  this  group  of  cases  it  is  easy  for  us  to  realize 
that  the  morbid  process  is  largely  confined  to  the  meninges  and 
to  the  surface  of  the  cortical  or  spinal  tissue,  but  the  spirochete 
can  no  doubt  be  reached  through  vascular  channels. 

"A  group  of  purely  spastic  palsies  with  very  slight  sensory 
changes,  with  httle  or  no  vesical  disturbance,  with  much  more 
rigidity  than  paralysis,  the  group  which  Erb  so  well  described 
and  which  is  long  since  recognized  as  a  purely  degenerative 
group,  yields  least  to  intravenous  or  to  any  other  forms  of  anti- 
syphilitic  medication.  The  question  of  the  effective  treatment 
is  most  in  doubt  when  we  come  to  consider  the  results  in  loco- 
motor ataxia.  The  tabetic  pains,  the  crises,  the  bladder  symp- 
toms, and  the  sexual  impotence,  may  be  relieved  by  antisyphilitic 
medication  as  we  have  known  them  to  be  relieved  by  prolonged 
periods  of  rest,  by  hydro-therapeutic  procedures,  by  mercurial 
injections,  by  almost  any  other  method  of  treatment  that  has 
from  time  to  time  been  advocated  for  the  treatment  of  tabes 
dorsalis." 


TREATMENT  OF  SYPHILIS  OF  CENTRAL  NERVOUS  SYSTEM  13 1 

A  Study  of  Four  Hundred  Cases 

Dr.  Sachs  gives  these  facts  to  show  why  he  has  pinned  his  faith 
to  the  intravenous  use  of  salvarsan,  or  neosalvarsan,  and  why  he 
has  rejected  the  more  dangerous  intraspinal  method  of  treatment. 
He  refers  to  an  article  by  his  associates,  Drs.  Kaliski  and  Strauss, 
on  "Syphilis  of  the  Nervous  System"  (Am.  Jour.  Syph.,  p.  609, 
October,  1918),  in  which  a  careful  critical  study  of  over  four  hun- 
dred cases  from  Sachs  service  is  considered. 

In  the  treatment  of  early  cerebrospinal  syphilis,  early  tabes 
dorsalis,  early  cases  of  Erb's  spastic  paraplegia  and  those  early 
cases  of  syphilis  without  nervous  symptoms  at  all  or  with  very 
persistent  cephalalgia  presenting  biological  changes  in  the  spinal 
fluid,  they  utilize  salvarsan  or  one  of  its  safe  substitutes.  The 
drug  is  given  intravenously  every  day  or  every  other  day  in 
doses  of  0.2  to  0.3  gram  until  a  total  of  from  i  gram  to  1.2  grams 
is  given  within  a  period  of  seven  days.  This  intensive  treatment 
can  be  safely  kept  up,  they  advise  us,  for  a  period  of  from  four  to 
eight  weeks,  nor  do  they  consider  it  necessary  to  give  the  drug 
more  than  three  times  a  week  for  more  than  from  four  to  six 
weeks.  On  alternate  days,  deep  intramuscular  injections  of 
bichloride  of  mercury  in  doses  of  Vs  grain  upwards  every  second 
or  third  day,  or  salicylate  of  mercury,  i  to  2  grains  every  fourth 
or  fifth  day  are  given. 

In  lesions  of  the  gummatous  type  the  authors  advise  the  use 
of  the  iodides,  30  to  60  grains  three  times  a  day,  in  addition  to 
the  salvarsan  treatment. 

Where  the  symptoms  are  not  so  urgent,  as  in  the  more  chronic 
cases  of  cerebrospinal  lues  and  tabes,  they  give  from  0.8  gram  to 
i.o  gram  of  salvarsan  each  week  with  or  without  injections  or 
inunctions  of  mercury. 

In  the  less  urgent  cases  the  intravenous  injections  are  kept 
up  from  six  to  eight  weeks.  At  the  end  of  this  time,  there  is  a 
rest  period  of  from  one  to  two  months. 

Drs.  Kaliski  and  Strauss  make  another  group  of  more  chronic 
cases,  especially  those  with  the  more  persistent  t3^e  of  cerebro- 
spinal lues  and  tabes,  with  persistent  positive  reactions  in  the 


132  THE  TREATMENT  OF  SYPHILIS 

blood  and  spinal  fluid,  and  with  mild  subjective  symptoms. 
They  administer  to  patients  in  this  group  salvarsan  from  0,3  to 
0.4  gram  twice  a  week  where  feasible,  or  possibly  every  fifth 
or  sixth  day  for  a  period  of  from  six  to  eight  weeks,  accompanied 
by  salicylate  of  mercury  injections  i  to  2  grains  every  fifth  day 
for  two  months,  or  they  utilize  inunctions. 

In  the  first  group,  after  the  disappearance  of  the  distinctive 
sjnnptoms,  they  do  not  believe  it  necessary  to  maintain  the  very 
intensive  salvarsan  therapy  for  the  full  period  of  eight  weeks, 
but  treat  the  patients  as  they  do  those  in  the  second  group  if 
improvement  has  been  satisfactory,  and  in  these  cases  they  give 
salvarsan  from  not  more  than  twice  a  week  to  three  times  a  fort- 
night. 

After  the  resumption  of  treatment,  following  the  rest  period, 
the  next  course,  they  say,  must  be  governed  entirely  by  the  nature 
of  the  symptoms.  If  there  is  pain,  paresthesias,  crises,  and  blad- 
der and  rectal  disturbances,  they  advise  a  second  course  of  sal- 
varsan intravenously  followed  by  mercury,  but  they  do  not  ad- 
minister salvarsan  oftener  than  once  a  week  in  doses  of  0.4  to 
0.5  gram  for  a  course  of  eight  injections.  They  remark  that  if 
they  use  neosalvarsan  a  third  larger  dose  in  every  instance  is 
given.  For  the  purpose  of  determination  of  the  condition  of 
the  spinal  fluid  in  cases  treated  only  intravenously  a  lumbar 
puncture  is  performed  once  or  preferably  twice  during  each 
course  of  treatment. 

Persistence  in  Treatment  Necessary 

Drs.  Kaliski  and  Strauss  emphasize  the  necessity  of  the  per- 
sistence in  treatment  after  the  initial  few  months  of  intensive 
therapy  for  from  one  to  two  years,  with  increasingly  greater 
intervals  between  treatments.  They  suggest  that  after  the  ces- 
sation of  active  symptoms  the  patient  should  report  from  once 
to  twice  a  year  for  observation  and  further  treatment,  because 
many  of  these  persons  not  only  have  a  lesion  of  the  nervous 
system  but  a  syphilitic  aortitis,  myocarditis,  endo-neuritis,  or 
some  other  condition  which  needs  watching. 

They  specify  a  third  group  in  which  they  place  cases  of  more 


TREATMENT  OF  SYPHILIS  OF  CENTRAL  NERVOUS  SYSTEM  133 

advanced  tabes  dorsalis,  late  cerebrospinal  lues,  optic  nerve 
atrophies,  spastic  paraplegias,  and  chronic  syphilitic  epilepsy. 
Destructive  lesions  involving  one  or  more  extremities  and  pain 
and  crises  may  be  the  predominating  factors  in  these  conditions, 
and  they  observe  that  they  can  frequently  bring  about  the  grad- 
ual aboUtion  of  pain  and  the  occasional  disappearance  of  the 
crises.  Optic  atrophy  cannot  be  cured  but  occasionally  can  be 
arrested,  although  they  are  not  optimistic  about  this  condition. 
Their  experience  has  shown  that  intravenous  therapy  aids  the 
ataxia  of  these  cases,  particularly  when  used  with  re-educational 
and  other  local  measures.  In  this  group  they  administer  sal- 
varsan  every  two  weeks  or,  on  occasion,  every  week,  in  doses  of 
0.4  to  0.5  gram  for  from  two  to  three  months  and  follow  it  by 
inunctions  or  injections  of  mercury.  If  ataxia  is  marked,  mer- 
cury by  injection  must  be  administered  with  care  and  for  that 
reason  they  prefer  the  inunctions. 

In  discussion  of  the  treatment  of  general  paresis,  Drs.  KaUski 
and  Strauss  are  of  the  opinion  that  so  far  as  the  use  of  salvarsan 
is  concerned,  they  are  not  yet  in  position  to  make  a  definite  state- 
ment on  account  of  the  lack  of  sufficient  data  and  the  brief 
period  of  observation  since  salvarsan  was  introduced.  They 
have  had  a  variety  of  results  in  the  treatment  of  this  condition, 
the  prognosis  of  which  is  uniformly  bad,  and  while  there  were 
some  patients  who  after  treatment  have  had  no  relapse  for  more 
than  two  years,  they  have  had  others  in  whom  the  treatment 
was  ineffective  in  bringing  about  much  improvement.  Their 
method  of  treatment  is  that  indicated  in  the  caring  for  the  con- 
ditions in  group  i. 

Syphilis   shows   few   Contraindications   to  Arsphenamine   and 

Mercury 

They  state  there  are  few  contraindications  to  the  use  of  ar- 
sphenamine and  mercury  in  the  treatment  of  syphiHs.  Optic 
neuritis  is  not  a  contraindication,  nor  is  optic  atrophy  necessarily 
one,  although  in  the  latter  condition  it  must  be  used  with  great 
care.  Cardiovascular  conditions,  particularly  when  accom- 
panied by  high  blood  pressure  and  renal  involvement  require 


134 


THE  TREATMENT  OF  SYPHILIS 


great  care  in  dosage  and  frequency  of  treatment.  They  remark 
that  the  prime  determining  factor  concerning  the  possibility  of 
arsphenamine  treatment  is  the  integrity  of  the  kidneys  and  they 
recommend  very  careful  urinary  examinations.  They  say  that 
"it  is  not  always  necessary  to  avoid  salvarsan  therapy  because 
of  the  presence  of  a  mild  nephritis,  but  where  treatment  is  given 
the  dosage  should  be  conservative  and  the  frequency  of  the  ad- 
ministration of  the  drug  such  as  to  permit  elimination  of  most 
of  the  arsenic  before  the  second  injection  is  given."  They  do  not 
give  salvarsan  more  than  once  in  two  weeks  in  these  conditions. 
They  also  note  that  certain  persons  have  a  hypersensitiveness 
to  arsphenamine,  a  phenomenon  which  usually  makes  itself 
manifest  after  two  or  three  injections.  They  think  the  patient 
has  been  sensitized  by  the  previous  injections,  and  that  the  re- 
actions are  due  to  the  toxic  action  of  the  drug  on  the  vasomotor 
system.  They  point  out  as  the  first  signs  of  the  anaphylactoid 
reaction  slight  dilatation  of  the  vessels  of  the  conjunctivae  or  skin, 
feeHng  of  warmth  in  the  face,  tickling  in  the  throat,  desire  to 
cough,  slight  abdominal  rumbhngs  or  cramps,  feeHng  of  fullness 
in  the  head,  or  difficulty  in  breathing  deeply.  They  advocate  the 
suspension  of  the  injection  without  the  withdrawal  of  the  needle. 
If  the  s5anptoms  are  progressive,  they  believe  in  discontinuing 
the  injection  but,  if  they  rapidly  pass,  they  advise  the  injection 
of  a  few  more  c.  c.  in  solution  and  finally  if  no  untoward  results 
follow,  the  injection  of  the  entire  amount.  At  the  time  of  sub- 
sequent injections  they  recommend  giving  these  patients  lo  or 
15  minims  of  a  1:1000  solution  of  adrenalin  subcutaneously  or 
i/ioo  grain  of  atropin  sulphate  fifteen  minutes  before  the  ar- 
sphenamine injection. 

Intravenous  First,  Intraspinal  Later 

Dr.  Richard  W.  Harvey  of  the  University  of  California  (Am. 
Jour.  Syph.,  p.  785,  1918)  in  a  study  of  cases  which  have  come 
under  his  care  at  the  University  Hospital,  San  Francisco,  be- 
lieves that  intravenous  arsenic  preparations  are  to  be  employed 
first  in  all  cases  of  nervous  system  lues,  accompanied  by  intra- 
muscular injections  of  mercury,  either  the  benzoate  or  salicylate, 


TREATMENT  OF  SYPHILIS  OF  CENTRAL  NERVOUS  SYSTEM  135 

or,  if  the  patient  is  in  the  hospital,  by  daily  inunctions.  Intra- 
spinal treatment  should  be  given  only  after  the  conservative 
treatment  has  been  employed  and  then  only  for  the  relief  of  pain 
and  of  crises  in  tabes  and  cerebrospinal  lues. 

Intra- Arterial  Injection  of  Neosalvarsan  in  Cerebrospinal 

Syphilis 

Dr.  David  A.  Sinclair  of  New  York  while  of  the  beUef  that 
salvarsan  is  the  most  powerful  spirocheticide  known,  feels  that 
its  beneficial  action  in  the  more  serious  affections  of  the  cere- 
brospinal system  has  not  been  demonstrated.  {Med.  Times, 
Vol.  XLV,  No.  I  and  No.  4,  pp.  18-89,  iQi?-)  His  belief  is  based 
on  the  difficulty  of  bringing  the  spirochetes  in  the  perivascular 
tissues  of  the  brain  and  spinal  cord  into  close  contact  with  the 
arsphenamine  introduced  by  ordinary  methods. 

A  careful  study  of  the  anatomy  of  the  brain  and  the  arrange- 
ment of  the  blood  supply,  he  says,  shows  this:  the  common 
carotid  artery  divides  into  the  internal  and  external  carotids. 
The  internal  ascends  directly  to  the  brain  and  gives  off  no 
branches  until  it  enters  the  skull.  With  its  fellow  of  the  opposite 
side  and  the  two  vertebral  arteries,  the  circle  of  Willis  is  formed 
through  the  anterior  and  posterior  communicating  arteries. 
Through  this  media  the  brain  receives  its  blood  supply.  The 
choroid  artery,  a  branch  of  the  internal  carotid,  supplies  the 
choroid  plexus  of  the  brain,  which  plexus  secretes  the  cere- 
brospinal fluid. 

Dr.  Sinclair's  contention  is  that  the  injection  of  neosalvarsan 
into  the  internal  carotid  artery  is  at  once  distributed  to  the  brain 
and  at  the  same  time  directly  feeds  the  secretory  apparatus  of  the 
cerebrospinal  fluid  through  the  choroid  artery. 

The  articles  quoted  from  the  Medical  Times  give  the  history 
of  a  case  in  which  Dr.  Sinclair,  after  some  animal  experimenta- 
tion, carried  out  his  belief  by  injecting  five  and  one-half  deci- 
grams of  neosalvarsan  into  the  internal  carotid  artery  in  a  pa- 
tient suffering  from  cerebrospinal  syphihs.  This  man  had  pre- 
viously been  given  intravenous  injections  of  neosalvarsan  on 


136  THE  TREATMENT  OF  SYPHILIS 

four  different  occasions  without  improvement  of  his  mental  con- 
dition, which  for  three  years  previous  had  caused  him  to  act  in  an 
extraordinary  manner.  Under  ether  anesthesia,  Dr.  Sinclair 
opened  the  tissues  of  the  neck  in  the  left  carotid  line  and  sep- 
arated the  internal  carotid  artery  from  the  jugular  vein  by  pass- 
ing a  grooved  director  underneath  it.  A  small  hypodermic 
needle  was  introduced  into  the  lumen  of  the  artery,  the  syringe 
attached  to  the  needle,  and  the  neosalvarsan  injected.  The 
wound  was  closed  by  chromicized  catgut  and  silkworm  gut 
sutures,  a  compress  placed  over  the  line  of  incision  and  all  held 
in  place  by  a  bandage.  The  man's  condition  improved  to  a  very 
considerable  extent.  Five  weeks  later  the  operation  was  re- 
peated and  nine  decigrams  of  neosalvarsan  in  10  c.  c.  of  distilled 
water  were  infused  into  the  right  internal  carotid  artery  by  the 
same  procedure.  Twenty-seven  days  thereafter  nine  decigrams 
of  neosalvarsan  in  10  c.  c.  of  water  were  given  ia  the  left  carotid 
artery.  After  that  there  was  marked  improvement  in  the  man's 
mental  and  physical  condition. 

Dr.  Sinclair  is  of  the  belief  that  therapeutic  medication  through 
the  arterial  system  offers  many  opportunities.  As  an  example, 
he  mentions  a  rebellious  syphilis  of  the  extremities.  He  beheves 
that  the  brachial  or  femoral  arteries  could  be  utiUzed  as  direct 
carriers  of  therapeutic  agents  and  thus  the  consequent  dilution 
which  must  occur  when  the  intravenous  route  is  used  would  be 
avoided. 

Intracranial  Salvarsan  Injection 

The  intracranial  method  of  the  introduction  of  salvarsan  is 
a  favorite  with  some  practitioners.  The  injection  is  either  intra- 
ventricular or  subdural. 

After  four  years  of  this  form  of  treatment,  Drs.  H.  A.  Cotton 
and  W.  W.  Stevenson  of  the  New  Jersey  State  Hospital,  Trenton, 
report  {Jour.  Ment.  df  Nerv.  Dis.,  1918)  that  the  intracranial 
method  is  the  most  eflBlcacious  mode  of  treatment  of  paresis,  and 
should  be  the  method  of  preference,  while  the  intraspinal  method 
is  the  most  efficient  one  for  the  treatment  of  tabes  and  luetic 
meningitis.    They  express  the  beHef  that  salvarsan  is  the  best 


TREATMENT  OF  SYPHILIS  OF  CENTRAL  NERVOUS  SYSTEM  137 

drug  for  the  treatment  of  cerebrospinal  syphilis  and  is  preferable 
to  the  substitutes.  They  urge  that  the  disease  should  be  di- 
agnosed in  the  pre-paretic  stage,  or  as  soon  as  the  symptoms  are 
present,  and  that  there  should  be  a  frequent  examination  of  the 
spinal  fluid  in  every  case  of  syphilis  after  all  symptoms  of  the 
acute  stage  are  lost,  especially  if  the  Wassermann  remains 
positive  after  sufficient  treatment  has  been  given. 

Arrest  and  Possible  Cure  of  Paresis 

They  conclude  that  all  cases  of  paresis  can  be  arrested  and 
possibly  cured  if  the  treatment  is  begun  early  enough. 

Drs.  Walker  and  Haller  {Arch.  Int.  Med.,  Sept.,  1916)  after  a 
study  of  seventy-five  cases  reach  the  conclusion  that  patients 
with  recent  syphihtic  meningitis  and  cerebrospinal  syphilis  may 
be  relieved  symptomatically  by  intravenous  injections  of  sal- 
varsan.  The  spinal  fluid  reaction  may  become  negative  with 
I  c.  c.  and  the  cell  count  may  become  normal.  Long  standing 
cases  of  cerebrospinal  syphiHs  and  tabes  are  likely  to  be  sympto- 
matically benefited  by  salvarsan  but  they  think  there  is  Httle  or 
no  change  in  the  spinal  fluid  findings. 

Patients  with  recent  as  well  as  late  syphilitic  meningitis, 
cerebrospinal  syphilis,  tabes,  and  general  paresis  are  markedly 
improved  following  intravenous  salvarsan  and  intraspinal  sal- 
varsanized  serum,  and  those  who  fail  to  improve  under  one  do 
improve  under  the  combined  treatment. 

Permeability  of  the  Meninges  to  Arsenic  in  Paresis  and  Tabes 

In  patients  who  have  received  intravenous  injections  of  sal- 
varsan or  neosalvarsan  it  has  been  demonstrated  that  the  serum 
contains  more  than  five  times  as  much  arsenic  as  the  clot.  Within 
thirty  miinutes,  about  75  per  cent  of  the  salvarsan  is  fixed  in  the 
body  cells  and  24  hours  after  the  intravenous  administration  of 
salvarsan,  it  is  found  that  arsenic  has  passed  into  the  spinal 
fluid. 

When  serum  treatment  is  used,  it  is  readily  observed  that  a. 
soluble  arsenic  preparation  formed  from  the  body  cells  is  being 


138  THE  TREATMENT  OF  SYPHILIS 

administered.  This  preparation  contains  the  larger  amount  of 
the  arsenic  which  remains  in  the  circulatory  system.  It  also 
suggests  the  need  of  drawing  the  blood  during  the  first  thirty 
minutes  after  the  intravenous  administration  of  the  drug  when 
it  is  to  be  used  as  a  source  of  serum  containing  arsenic. 


CHAPTER  XIII 

THE    TREATMENT    OF    CONGENITAL,    MALIGNANT    AND    VISCERAL 

SYPHILIS 


Congenital  Syphilis 

Various  plans  for  the  treatment  of  congenital  syphilis  are  in 
vogue,  and  most  syphilologists  have  their  own  methods  of 
procedure. 

A  logical  plan  has  been  devised  by  Eugene  Graetzer  and  is  de- 
scribed {Urol.  ^  Cut.  Rev.,  September,  1916)  as  a  course  or  a  series 
of  courses  of  neosalvarsan  and  calomel. 

A  single  course  consists  either  of  12  calomel  and  8  neosal- 
varsan injections,  or  of  six  weekly  inunctions  and  eight  neosal- 
varsan injections.  The  courses  occupy  approximately  a  period 
of  three  months. 

The  combined  calomel-neosalvarsan  course  is  applied  accord- 
ing to  the  following  scheme : 


Week 

Treatment 

I 
2 

Two  calomel  injections, 
ist  and  2nd  neosalvarsan  injections. 

sj 

6 

7 
8 

3rd  and  4th  calomel  injections. 
3rd  and  4th  neosalvarsan  injections. 

5th  and  6tli  calomel  injections. 
5th  and  6th  neosalvarsan  injections. 

9 
10 
II 

7th  and  8th  calomel  injections. 
7th  and  8th  neosalvarsan  injections. 

13 
14 

9th  and  loth  calomel  injections, 
nth  and  12th  calomel  injections. 

I40 


THE  TREATMENT  OF  SYPHILIS 


Following  this  first  course  there  comes  a  rest  for  three  months, 
after  which  the  second  course  begins  in  the  same  way;  and,  after 
a  second  rest  for  three  months,  the  third  course  in  the  same  pro- 
portions takes  place.  The  combined  inunction  and  neosalvarsan 
cure  is  applied  as  follows: 


Week 

Treaimeni 

I 

2 

3 

Inunction  course  (i  week). 

ist  and  2nd  neosalvarsan  injections. 

Inunction  course  (2  weeks). 

4 
5 
6 

7 
8 

3rd  and  4th  neosalvarsan  injections. 

Inunction  course  (3  weeks). 

5  th  and  6th  neosalvarsan  injections. 

9 

lO 

II 

Inunction  course  (4  weeks). 

7  th  and  8th  neosalvarsan  injections. 

13 

14 

Inunction  course  (5  and  6  weeks). 

From  the  second  year  on,  calomel  and  inunctions  are  alternated. 
In  infancy,  because  of  the  small  surface  and  the  sensitiveness  of 
the  skin,  it  is  better  to  avoid  inunctions.  Dosage,  according  to 
Graetzer,  is  as  follows:  o.ooi  g.  calomel  and  0.015  §•  neosalvar- 
san per  kilogram  of  body  weight.  Of  course,  the  fijst  injection 
of  neosalvarsan  is  less  than  given  in  the  scale  in  order  that  idiosyn- 
crasies may  be  ascertained.    The  author  has  never  observed  any. 

As  a  site  for  injecting  the  calomel  and  also  for  the  epifascial 
injections  of  neosalvarsan,  he  recommends  the  thick  musculature 
of  the  nates  in  the  upper  external  quadrant.  The  calomel  in- 
jections can  also  be  injected  into  the  upper  Hmb.  The  neosalvar- 
san is  usually  applied  intravenously  in  infants,  either  into  the 
veins  of  the  skull,  the  ankle-joint,  the  jugular,  or  recently,  ac- 
cording to  L.  Tobler,  into  the  sinus  longitudinaHs.  This  last 
mentioned  method  proved  to  be  very  satisfactory,  but  it  is  a 
hospital  procedure  which  limits  its  field  of  usefulness.    Only  in 


CONGENITAL,  MALIGNANT  AND  VISCERAL  SYPHILIS    141 

exceptional  cases  should  infants  receive  neosalvarsan  injections 
intramuscularly.  The  author  keeps  on  hand,  3,  4,  5  per  cent 
solutions  of  calomel  in  olive  oil.  With  large  children  he  uses  pref- 
erably the  40  per  cent  calomel  solution  of  Zichler. 

He  says  "the  dosage  of  the  grey  ointment  for  the  inunction 
course  is  at  the  rate  of  i.o  grm.  of  ointment  to  10  kg.  body  weight 
and  should  not  exceed  4.0  g.  A  child  weighing  20  kg.  gets  six 
inunctions  of  2  g.  per  week  and  on  the  7th  day  is  bathed." 

Treatment  of  the  Expectant  Mother 

Many  men  favor  treatment  of  the  expectant  mother,  if  she  or 
her  husband  be  syphilitic,  in  the  hope  of  preventing  a  luetic 
child.  This  plan  consists  of  intensive  treatment  with  salvarsan 
or  neosalvarsan,  mercurial  inunctions  and  the  iodides. 

Dr.  Lisser  {Cal.  State  Jour.  Med)  beheves  it  to  be  wiser,  if  the 
treatment  is  begun  during  the  early  months  of  pregnancy,  to 
employ  frequent  small  doses  of  salvarsan,  0.2  to  0.3  to  0.4  gram, 
rather  than  the  full  dose,  although  it  has  been  shown  that  sal- 
varsan does  not  seem  to  increase  the  tendency  to  abortion  or 
hemorrhage.  But  the  total  amount  of  salvarsan  should  be  at 
least  1.5  grm,,  and  larger  amounts  are  safer. 

Such  treatment  affects  the  fetus  favorably  by  its  curative 
action  on  the  mother,  and  in  the  early  stages  especially,  by  pre- 
venting disease  of  the  placenta.  Furthermore,  Meyer  has  shown 
in  the  case  of  salvarsan,  that  whereas  a  normal,  sound  placenta 
does  not  allow  arsenic  to  permeate,  the  syphiHtic  placenta  does 
permit  the  drug  to  pass  through  to  the  fetus. 

Findlay  and  Robertson  {Glasgow  Medical  Journal)  record 
several  successful  examples  of  such  antenatal  therapy.  "In  no 
case  was  the  course  of  the  pregnancy  interrupted,  and  the  mothers 
did  not  seem  to  suffer  much  from  the  treatment.  The  mothers, 
as  a  rule,  expressed  themselves  as  feeling  better  during  these  than 
during  any  of  their  previous  pregnancies." 

So  far  as  their  experience  goes,  equally  good  results  were 
obtained  whether  treatment  was  commenced  as  early  as  the 
second  month  or  delayed  the  seventh  month  of  pregnancy.  ' '  This 
in  all  probability  is  to  be  accounted  for  by  the  fact  that  many 


142  THE  TREATMENT  OF  SYPHILIS 

syphilitic  infants  are  infected  during  parturition,  the  mischief 
remaining  local  in  the  placenta  during  the  whole  course  of  ges- 
tation. It  is  this  uterine  localization  of  the  disease  which  ac- 
counts for  the  absence  of  clinical  manifestations  in  many  of  the 
mothers  of  syphiHtic  children.  Baisch,  Trinchese,  and  Weber 
working  in  Doderlein's  clinic,  found  that  in  the  case  of  every 
syphilitic  child  the  placenta,  both  the  fetal  and  maternal  por- 
tions, contained  spirochetes,  and  in  common  with  Rietschel  are 
inclined  to  the  opinion  that  the  spirochete  always  travels  to  the 
child  from  the  placenta. 

"Most  authorities  agree  that  during  gestation  the  spirochete 
may  travel  along  the  umbilical  cord  and  infect  the  fetus,  but 
this  according  to  Rietschel  is  less  frequent  than  infection  by 
emboli  set  free  during  parturition.  It  would  therefore  seem  ex- 
ceedingly likely  that  in  the  treatment  of  pregnant  women  the 
salvarsan  gets  easily  at  the  very  vascular  placenta  and  destroys 
the  contagimn  vivum,  thus  considerably  lessening  the  risk  of 
embohsm  from  living  spirochetes." 

Antenatal  Treatment  Versus  no  Therapy 

It  is  interesting  to  compare  the  statistics  of  such  antenatal 
therapy  with  the  results  of  no  therapy  at  all.  With  no  treatment 
of  maternal  syphilis  at  all,  the  primary  mortaUty  of  congenital 
syphilis  is  enormous.  In  the  first  year  of  Hfe,  Leduc  estimates 
it  at  71  per  cent;  Zeissl  at  80  per  cent;  Bunch  at  90  per  cent; 
Markus  at  90  per  cent.  Hochsinger  claims  that  93  per  cent,  of 
syphilitic  children  have  disease  of  the  nervous  system. 

According  to  Galliot,  when  mothers  are  treated  before  preg- 
nancy, but  not  during  pregnancy,  82  per  cent  of  the  resulting 
children  are  born  dead. 

Mercurial  treatment  of  the  pregnant  mother  has  the  following 
results  to  commend  it:  Of  217  infected  pregnant  women  showing 
signs  of  active  syphilis  during  their  pregnancy,  who  were  vigor- 
ously treated  with  mercury  and  iodides  during  their  pregnancy, 
25  per  cent  of  the  resulting  progeny  were  bom  alive,  of  whom 
10  per  cent  showed  signs  of  syphilis.  This  is  at  once  a  striking 
improvement  over  no  treatment  at  all. 


CONGENITAL,  MALIGNANT  AND  VISCERAL  SYPHILIS    143 

Of  163  pregnant  infected  women,  without  signs  of  active  lues, 
but  having  so-called  latent  lues,  who  likewise  were  vigorously 
treated  with  mercury  and  iodides  during  their  pregnancy,  66 
per  cent  living  children  were  bom  who  were  well  clinically;  14 
per  cent  were  bom  alive  but  showed  signs  of  congenital  lues,  and 
19  per  cent  were  born  dead.  Pinard,  Champetier  de  Ribes,  and 
Potocki,  by  prolonged  treatment  with  mercury  and  potassium 
iodid,  obtained  76  per  cent  of  the  children  healthy. 

Of  128  women  with  latent  lues,  who  were  treated  before  and 
during  pregnancy  with  mercury  and  iodides,  88  per  cent  living 
children,  clinically  well  resulted,  the  remainder  showing  signs  of 
syphilis.  These  statistics  are  surely  a  strong  argument  in  favor 
of  the  thorough  treatment  of  the  disease  (Galliot). 

Fleeting  Character  of  Mercury 

But  the  effect  of  mercury  unless  continued  is  fleeting.  This 
is  illustrated  in  an  astonishing  manner  by  the  following  case 
reported  by  Foumier  (Meyer).  A  syphilitic  woman  was  preg- 
nant eleven  times.  She  had  no  treatment  whatsoever  during 
the  first  seven  pregnancies,  and  the  result  was  seven  dead  luetic 
children.  During  the  eighth  and  ninth  pregnancies,  energetic 
mercurial  treatment  was  given,  and  the  result  was  two  healthy 
children.  No  treatment  was  taken  during  the  tenth  pregnancy 
and  again  a  luetic  child  was  born  dead.  Treatment  during  the 
eleventh  pregnancy  was  successful  in  bringing  forth  a  healthy 
child.  Foumier  concludes:  "So  powerful  yet  so  fleeting  is  the 
effect  of  mercury  that,  if  it  were  not  immoral,  I  would  like  to 
try  the  experiment  of  alternately  treating  and  not  treating  a 
syphilitic  mother,  and  alternately  bringing  into  the  world  healthy 
and  syphilitic  children." 

Advantages  of  Salvarsan 

When  salvarsan  was  combined  with  such  mercurial  therapy, 
remarkable  results  were  obtained,  Sauvage  reporting  93  per  cent 
and  Bourret  and  Fabre  100  per  cent  cures.  These  latter  statis- 
tics may  be  somewhat  enthusiastic,  for  it  must  be  admitted 
that  many  cases,  showing  congenital  syphiHs  after  reaching  6  to 


144  THE  TREATMENT  OF  SYPHILIS 

20  years  of  age,  showed  no  specific  manifestations  whatsoever 
during  the  first  few  years  of  life.  Most  of  the  cases  reported 
were  only  observed  during  the  first  few  months  or  first  year  of 
life,  and  are  therefore  subject  to  this  reservation.  Nevertheless, 
it  would  seem  that  this  method  of  antenatal  therapy  has  much  to 
support  it  and  merits  extensive  trial. 

Dr.  Lisser  notes  that  another  prophylactic  measure  suggests 
itself.  Suppose  that  an  apparently  healthy  child,  with  negative 
Wassermann  and  negative  luetin,  is  born  from  parents  known  to 
have  active  syphilis.  In  view  of  the  fact  above-mentioned,  that 
luetic  stigmata  do  not  develop  in  certain  cases  until  long  after 
infancy,  would  it  not  be  prudent  to  administer  small  doses  of 
mercury  intermittently  to  such  a  child  during  the  first  few  years 
of  Hfe?  In  reasonable  quantities  such  therapy  would  not  be 
harmful.  It  might  be  beneficial.  It  is  almost  impossible  to  bring 
facts  or  statistics  in  favor  of  such  a  procedure,  for  the  unanswer- 
able criticism  can  always  be  advanced  that  the  particular  child 
so  treated  may  never  have  developed  syphilis  anyway.  But 
when  one  bears  in  mind  the  extraordinary  obstinacy  of  just 
those  cases  where  the  disease  makes  its  appearance  late  in  child- 
hood, it  would  at  least  appear  to  be  an  error  on  the  side  of  safety 
to  treat  prophylactically  infants  who  are  the  progeny  of  parents 
recently  tainted  with  syphilis. 

Old  salvarsan,  unfortunately,  has  not  the  wide  appHcation  in 
congenital  syphihs  that  it  has  in  the  acquired  form.  Dr.  Lisser 
goes  on  to  say,  not  because  it  is  less  efficacious,  but  because  of  the 
difficulties  of  administration.  Even  in  acquired  syphihs  its 
intramuscular  use  has  been  largely  abandoned,  the  pain  resulting 
from  the  injection  and  the  necrosis  and  sloughing  that  not  in- 
frequently supervene  are  very  serious  objections;  and  in  children 
the  dehcacy  of  the  tissues  should  absolutely  prohibit  its  use  in 
this  way.  However,  salvarsan  can  and  should  be  used  intraven- 
ously whenever  there  is  a  vein  of  sufficient  size  at  the  bend  of  the 
elbow.  It  should  be  well  diluted  and  the  consequent  large  amount 
of  fluid  to  be  injected  must  be  allowed  to  flow  into  a  vein  in  a 
position  where  the  flow  can  be  easily  controlled. 

The  jugular  vein  has  been  used  and  likewise  the  veins  of  the 


CONGENITAL,  MALIGNANT  AND  VISCERAL  SYPHILIS    145 

scalp,  but  whereas  these  routes  are  excellent  in  the  case  of  neo- 
salvarsan  where  highly  concentrated  solutions  can  be  used  and 
the  operation  quickly  finished,  it  is  difficult  to  keep  the  child 
quiet  enough  for  a  sufficiently  long  period  of  time  to  permit  the 
steady  flow  of  50  to  100  c.  c.  as  is  the  case  when  salvarsan  is  used. 
In  view  of  the  frequency  of  these  injections  it  does  not  seem  ad- 
visable to  anesthetize  the  child,  particularly  when  other  effica- 
cious drugs  are  available.  Salvarsan  should  only  be  given  in- 
travenously, and  only  into  a  vein  of  the  forearm.  Its  dosage 
must  be  regulated  according  to  the  age  and  size  of  the  patient, 
and  the  fijst  dose  should  always  be  exceedingly  small.  Even  in 
the  adult,  there  is  a  growing  tendency  to  use  smaller  individual 
doses,  especially  the  initial  dose;  that  is  from  0.2  to  0.4  gram  in- 
stead of  0.6  gram.  It  is  evident  that  much  greater  caution  is 
necessary  in  young  children;  o.oi  gram  to  every  kilo,  or  2>^ 
lbs.,  is  a  safe  average.  It  is  probably  a  safe  custom  to  place  such 
children  in  a  hospital  over  night.  Lisser  believes  that  in  the  com- 
paratively few  cases  where  salvarsan  can  be  used,  the  results  are 
highly  satisfactory.  Just  as  in  acquired  lues,  mercury  should 
invariably  be  used  in  combination  with  the  salvarsan.  Neither 
alone  is  as  reliable  as  both  together. 

A  Wider  Field  for  Neosalvarsan 

Neosalvarsan  has  a  wider  field  of  usefulness  in  congenital 
syphilis  than  in  the  acquired  form,  Lisser  observes,  and  for  the 
following  reasons:  Its  use  in  acquired  lues  is  largely  a  matter  of 
convenience,  and  can  be  entirely  displaced  and  should  be  dis- 
placed by  the  more  powerful  effect  of  old  salvarsan.  But  in 
inherited  lues  it  is  invaluable  because  of  the  high  concentration 
in  which  it  may  be  injected. 

It  can  be  employed  in  two  ways:  first,  intravenously,  using  the 
veins  of  the  scalp,  as  first  suggested  by  Neogarrath  in  191 1. 
This  is  the  method  of  choice  in  infants  up  to  about  two  years  of 
age.  Simpson  and  Thatcher  in  1913  advocated  the  use  of  the 
external  jugular,  but,  in  the  technic  they  describe,  an  anesthetic 
is  necessary,  the  vein  being  cut  down  upon  and  a  cannula  in- 
serted.   Such  a  drastic  procedure  was  justified  at  the  time  when 


146  THE  TREATMENT  OF  SYPHILIS 

it  was  thought  that  one  large  dose  would  cure  the  disease,  but 
since  experience  has  demonstrated  the  necessity  of  frequently 
repeated  injections,  it  would  be  wiser  to  use  other  methods  at 
our  disposal.  By  utilizing  the  veins  of  the  scalp,  neosalvarsan 
can  be  given  in  3  or  4  c.  c.  of  saline  or  freshly  distilled  water  in  an 
ordinary  Record  or  Luer  syringe,  and  in  a  very  few  minutes.  The 
initial  dose  should  be  calculated  from  0.015  gram  per  kilo;  that  is 
about  0.05  gram  for  a  new-born  infant,  gradually  increasing  in 
successive  doses  to  0.2  or  even  0,3  gram  per  injection.  This 
dosage  has  been  used  with  safety  and  success.  Slight  reactions 
such  as  vomiting,  diarrhea,  and  occasionally  fever  will  result,  but 
no  more  so  and  no  more  serious  than  occurs  frequently  in  adults. 

Epifascial  Method  of  Injection 

Wechselmann's  so-called  epifascial  method  of  injection  is 
serviceable  in  those  children  between  the  ages  of  2  and  7,  who 
have  neither  veins  of  the  scalp  for  intravenous  neosalvarsan 
nor  veins  of  the  forearm  for  old  salvarsan.  Wechsehnann  em- 
ploys it  in  his  routine  treatment  of  adults,  never  giving  neosal- 
varsan intravenously,  but  only  epifascially,  and  reserving  the 
veins  for  old  salvarsan.  The  technic  requires  some  practice,  but 
once  learned,  is  really  very  simple,  quick,  and  convenient. 

Mercury  is  as  valuable  in  the  treatment  of  inherited  syphilis 
as  salvarsan.  To  omit  its  use  would  be  an  error.  The  official  blue 
ointment  may  be  used.  The  skin  of  children  will  not  permit 
vigorous  rubbing  nor  is  it  necessary.  Inunctions  should  be  given 
six  days  out  of  the  week.  In  very  small  children  and  infants 
bichlorid  baths  are  very  satisfactory.  Twenty  or  thirty  grains 
of  bichlorid  mixed  with  an  equal  quantity  of  ammonium  chloride 
should  be  used. 

Oral  medication  is  not  satisfactory  for  several  reasons.  Ab- 
sorption from  the  intestinal  tract  is  imcertain  and  if  the  parent  is 
in  charge  of  the  treatment,  doses  may  be  given  irregularly,  and 
when  taken  faithfully  derangements  of  the  intestinal  tract  are 
not  uncommon.  The  gray  powder,  mercury  with  chalk,  in  doses 
of  yi-yi  gr.,  or  calomel  gr.  1/10-1/4  t.  i.  d.,  is  probably  as  good 
as  any  of  the  many  preparations. 


CONGENITAL,  MALIGNANT  AND  VISCERAL  SYPHILIS    147 

The  Value  of  the  Iodides 

Lisser  insists  that  the  iodides  occupy  an  important  place  in  the 
specific  therapy  of  congenital  syphilis.  They  should  be  given 
far  more  frequently  than  is  generally  the  case^  and  their  mode  of 
action  and  precise  value  should  be  more  clearly  appreciated. 
The  iodides  should  never  be  given  without  mercury  or  salvarsau. 
The  destruction  of  the  causative  organism  is  accompKshed  by 
the  mercury  and  salvarsan,  but  the  wreckage  that  results  is 
swept  away  by  the  iodides.  They  occupy  a  singular  role,  there- 
fore, in  supporting  and  completing  the  work  of  the  destroyers. 
The  function  of  the  iodides  is  to  dissolve  and  eliminate.  Although 
their  most  spectacular  efficiency  is  demonstrated  in  the  tertiary 
processes  where  gummas  are  magically  made  to  vanish  under 
their  influence,  they  should  Hkewise  be  used  in  the  earher  stages 
of  the  disease,  for  the  principle  of  their  action  remains  the  same, 
and  it  is  at  aU  times  beneficial  to  aid  in  the  elimination  of  the 
syphilitic  poison. 

The  two  commonest  preparations  of  the  iodides  are  the  sat- 
urated solution  and  the  combination  in  Hquid  form  with  mercury 
in  the  so-called  "mixed  treatment."  When  exceptional  cir- 
cumstances demand  the  use  of  mercury  by  mouth,  this  mixed 
treatment  is  quite  satisfactory.  It  must  be  remembered  that 
only  the  bichlorid  or  bim'odid  should  be  used  in  such  a  mix- 
ture, for  the  proto  salts  are  changed  by  the  iodides  into  the 
binary  forms,  making  a  more  powerful  and  perhaps  dangerously 
high  dosage.  If  mercury  is  given  in  pill  form,  it  should  be  taken 
an  hour  before  meals,  and  the  potassium  iodid  an  hour  after 
meals,  so  that  the  former  will  have  left  the  stomach  before  the 
latter  arrives. 

As  a  routine  preparation  the  saturated  solution  is  very  satis- 
factory. It  should  always  be  given  in  high  dilutions,  preferably 
in  a  large  glass  of  milk,  always  after  meals,  as  it  irritates  an 
empty  stomach,  and  in  much  higher  dosage  than  is  generally 
prescribed.  The  usual  dosage  for  adults  will  not  be  high  for  Httle 
children,  namely  30-45  grains  per  day,  and  it  is  far  too  low  for 
adults.     Probably  httle  good  is  accomplished  in  adults  under 


148  THE  TREATMENT  OF  SYPHILIS 

75  grains  per  day,  and  many  cases  require  several  hundred 
grains  per  day.  So  for  children  an  initial  dose  of  5  grains  t.  i.  d.  is 
quite  conservative  and  should  be  rapidly  increased.  lodism  is 
more  common  with  small  doses  of.  potassium  iodid  than  with 
enormous  doses. 

Malignant  Syphilis 

Arsphenamine  plays  the  leading  role  in  the  treatment  of  this 
condition,  which  is  characterized  by  rapid  destruction  of  tissue, 
following  marked  skin  ulcerations  and  results  in  the  permanent 
formation  of  gummata.  The  process  attacks  chiefly  the  scalp, 
face  and  hmbs,  may  affect  the  oral  cavity  and  sometimes  leads  to 
bone  necrosis. 

A  marked  characteristic  of  malignant  syphilis  is  intolerance  to 
mercurial  treatment.  Patients  easily  become  salivated  and  the 
drug  is  practically  contraindicated,  particularly  during  the  early 
stages  of  the  disease. 

Salvarsan  is  usually  well  borne  and  has  proved  very  effective. 
Its  use  as  a  spirocheticide  is  the  one  bright  and  shining  feature  in 
the  treatment  of  this  severe  condition,  and  potassium  iodid  should 
be  employed  in  heroic  doses  to  aid  in  the  absorption  of  gum- 
matous infiltrations. 

The  hygiene  of  these  patients  must  be  watched  carefully  and 
they  must  have  every  advantage.  The  diet  should  be  nourishing 
and  stimulating,  tonics  such  as  quinin  and  iron  are  to  be  adminis- 
tered, and  sea  water  bathing  is  advised.  In  addition  the  patient 
must  live  in  the  open  air. 

The  local  treatment  of  the  ulcers  consists  in  bathing  with 
potassium  permanganate  or  some  equally  efficient  non-toxic 
disinfectant  and  dusting  the  sores  with  a  pure,  bland  powder. 

Proper  hygiene,  salvarsan  and  potassium  iodid  will  usually 
prove  effective  in  malignant  syphilis. 

Tertiary  Lesions  of  the  Viscera 

When  syphihs  has  invaded  the  vital  organs  of  the  body  as 
the  result  of  insufficient  or  improper  treatment,  in  the  form  of 
syphilitic   endarteritis,   periarteritis   and   infiltration,   vigorous 


CONGENITAL,  MALIGNANT  AND  VISCERAL  SYPHILIS    149 

treatment  must  be  instituted  to  kill  the  treponemata  and  absorp 
the  infiltrations. 

The  method  of  procedure  in  these  cases,  according  to  Dr. 
Harlow  Brooks  of  New  York  {N.  Y.  State  Jour.  Med.,  April  15, 
191 6),  should  differ  from  the  usual  routine. 

The  treatment  of  syphilitic  aortitis,  aneurism  and  heart  con- 
ditions includes  at  first  several  intramuscular  injections  of  salicy- 
late of  mercury.  Then  intravenous  injections  of  salvarsan  may 
follow,  the  first  being  0.3  gram  and  the  dose  is  to  be  increased 
if  no  untoward  results  ensue.  The  course  of  treatment  is  con- 
cluded by  the  employment  of  potassium  iodid  in  increasing  doses. 

The  purpose  of  the  iodid  is  to  absorp  the  newly  formed  gum- 
matous tissue. 

Especial  attention  is  directed  to  the  necessity  of  using  mer- 
cury for  several  weeks  before  commencing  the  arsphenamine 
treatment. 


CHAPTER  XIV 

SYPHILITIC  RE-mrECTION 

The  impression  is  becoming  more  and  more  firmly  established 
that  there  is  no  such  thing  as  a  general  natural  immunity  from 
syphilis.  The  one-time  belief  that  one  syphilitic  infection  brought 
about  immunity  from  further  infection  has  been  broken  down 
by  cases  of  actual  re-infection  which  have  come  to  the  attention 
of  the  great  bulk  of  the  syphilologists  of  this  country  from 
time  to  time. 

The  treatment  of  syphilis  by  means  of  salvarsan  has  un- 
doubtedly had  some  effect  in  this  connection.  Under  the  old 
method  of  treatment  it  is  probable  that  a  great  number  of  the 
so-called  cured  cases  of  syphihs  were  not  cured.  When  one  of 
those  uncured  cases  showed  luetic  symptoms  the  second  time  it 
was  doubtless  an  outbreak  of  the  original  condition.  For  this 
reason  cases  of  re-infection  were  so  very  exceptional  that  the 
profession  had  good  reason  to  believe  that  there  was  no  such  thing 
as  re-infection. 

We  now  believe  that  syphilis  properly  treated  can  be  cured, 
and  it  is  very  apparent  that  re-infection  does  not  take  place 
until  the  initial  infection  has  been  absolutely  cured. 

A  considerable  number  of  cases  of  re-infection  have  been  re- 
ported in  medical  literature  during  the  last  few  years.  General 
acceptance  of  these  conditions  enables  the  physician  to  judge  as 
to  positive  proof  of  re-infection,  if  spirochetae  are  found  in  a 
new  chancre  appearing  in  a  different  site  from  the  original  lesion 
and  if  the  blood  gives  a  negative  Wassermann  reaction.  This,  of 
course,  is  predicated  upon  the  attack  being  seen  shortly  after 
the  appearance  of  a  lesion  as  well  as  upon  the  discovery  in  the 
first  attack  of  the  spirochetae  with  all  the  presence  of  syphilitic 
lesions,  such  as  the  rash,  mucous  patches,  or  condylomata,  or  a 
positive  Wassermann  reaction  which  has  not  been  the  result  of 
hereditary  syphiUs. 


SYPHILITIC  RE-INFECTION  151 

Major  C.  F.  White,  R.  A.  M.  C,  reports  {Brit.  Med.  Jour., 
Oct.  20, 191 7)  a  series  of  cases  in  which  the  first  attack  was  treated 
with  salvarsan  and  mercury  and  a  cure  effected,  in  his  beh'ef. 
At  a  later  period  there  was  what  seemed  to  be  a  re-infection, 
hving  up  to  the  conditions  heretofore  mentioned,  and  these  were 
treated  with  salvarsan  and  mercury  and,  to  the  best  of  his  behef, 
also  were  cured. 

He  also  reports  another  series  in  which  the  second  attack  did 
not  live  up  to  the  bacteriological  findings  and  the  necessary 
serum  tests,  but  he  believes  them,  nevertheless,  to  have  been 
cases  of  re-infection,  as  each  one  of  these  cases  had  been  seen  by 
him  during  both  the  attacks. 

In  the  treatment  of  10,500  cases  of  syphilis  in  two  years,  Lt. 
Col.  Harrison  saw  28  cases  of  re-infection.  Additional  cases 
could  be  quoted  but  these  will  suffice  to  show  the  physician  that 
he  must  bear  the  possibiHty  of  re-infection  in  mind  in  the  treat- 
ment of  various  cases  of  syphilis. 


CHAPTER  XV 


THE   CURE   OF   SYPHILIS 


The  day  has  not  yet  arrived  for  any  chnician  to  attempt  to 
establish  a  definite  standard  of  cure  of  S3rphilis.  The  old  method, 
in  which  the  physician  gave  mercury  and  iodides  over  a  period  of 
years  and  then  pronounced  the  cases  cured,  has  been  relegated  to 
the  discard.  Sufficient  time  has  not  elapsed  since  the  introduc- 
tion of  606  to  permit  us  to  have  an  absolute  knowledge  as  to  the 
lasting  effects  of  arsphenamine  upon  the  spirocheta  pallida.  The 
spirochete  may  have  resting  periods;  it  may  possess  arsenical 
tolerance,  particularly  when  we  know  that  cases,  which  seem  to 
have  been  arrested,  if  not  cured,  still  continue  positive.  We 
beHeve  that  eternal  vigilance  is  necessary  in  the  consideration  of  a 
"cure"  and,  as  elsewhere  expressed,  we  should  for  a  period  of 
years  follow  up  these  cases  and  watch  them  carefully  through  the 
eyes  of  the  Wassermann  reaction. 

The  Standard  of  Cure  of  Syphilis 

Oswald  Dinm'ck,  of  the  Royal  Free  Hospital  of  London  {Lan- 
cet, June  21,  1919)  in  an  instructive  lecture  before  the  London 
School  of  Medicine  for  Women,  set  forth  as  his  beh'ef  that  if, 
after  an  intensive  course  of  arsenical  medication  and  the  con- 
tinuous exhibition  of  mercury  for  two  years,  a  patient  can  show 
two  years'  freedom  from  physical  signs  of  disease,  has  a  per- 
sistently negative  blood  serum,  a  spinal  fluid  which  shows  no 
variation  from  normal  in  either  pressure,  globulin  content,  or 
cellular  count,  and  which  gives  a  negative  Wassermann  in 
amounts  of  2  c.  cm. ;  and,  if  after  a  period  of  freedom  from  treat- 
ment, these  conditions  are  still  present  and  persist  in  spite  of 
provocative  treatment,  it  is  justifiable,  in  our  present  state  of 
knowledge,  to  presume  this  patient  cured. 


THE  CURE  OF  SYPHILIS  153 

Finally,  should  this  patient  subsequently  develop  a  fresh 
chancre,  at  a  site  differing  from  the  first,  this  would  be  a  re- 
infection, and  would  prove  our  contention.  For  syphilis  does  not 
confer  immunity,  and  the  real  interpretation  of  all  alleged  im- 
munity is  that  the  so-called  immune  person  is  an  active  syphiUtic, 

Wechsehnann,  in  his  Salvarsan  Therapy,  Volume  2,  page  no, 
sets  forth  conditions  of  cure  which  are  accepted  by  many  persons 
as  authority.  According  to  him,  cure  is  effected  when  the  patient 
is  free  from  symptoms  of  the  skin,  mucous  membrane,  and  all 
inner  organs;  when  his  blood  serum  no  longer  shows  a  positive 
Wassermann  reaction;  when  his  lumbar  puncture  shows  no  al- 
terations, and  if  this  absence  of  all  positive  signs,  especially  the 
negative  Wassermann  and  the  negative  lumbar  puncture,  remains 
permanent  upon  most  careful  control  for  a  certain  period  of  time. 

Wechsehnann  says  that  this  particular  period  is  generally  ac- 
cepted as  one  year,  although  this  is  not  absolute.  He  advises  the 
taking  of  the  blood  for  the  Wassermann  at  from  two  to  four- 
month  intervals  and  that  a  spinal  puncture  should  be  made  at 
less  frequent  intervals. 

We  believe  that  Wechselmann's  time  h'mit  is  too  short  and 
are  much  more  incHned  to  accept  Dinnick's  views  that  the  pa- 
tient should  show  two  years'  freedom  from  physical  and  serologi- 
cal signs. 

Prevention  of  Infection  of  the  Operator 

Some  physicians  exercise  little  or  no  precaution  against  in- 
fecting themselves  while  administering  arsphenamine  and  neo- 
arsphenamine. 

It  must  be  borne  in  mind  that  the  blood  of  all  syphilitics  is 
infectious,  that  of  persons  in  the  primary  and  secondary  stages 
being  more  capable  of  conveying  the  infection  than  that  in 
tertiary  and  latent  stages. 

It  is  agreed  that  the  chancre  and  the  mucous  patch  are  much 
more  fertile  fields  of  infection  than  the  blood,  but  as  all  these 
sources  readily  transmit  the  treponemata,  the  physician  should 
protect  his  hands  with  rubber  gloves  and  as  a  double  precaution 


154  THE   TREATMENT   OF   SYPHILIS 

he  should  employ  collodion  about  the  finger  nails  in  the  event  of 
the  presence  of  a  hang  nail  or  an  abrasion. 

Penetration  of  the  operator's  hand  or  finger  by  a  used  salvar- 
san  needle  should  be  followed  by  an  immediate  lading  open  on  the 
part,  after  first  shutting  off  the  blood  supply,  and  the  application 
of  pure  phenol.  The  introduction  of  an  injection  of  arsphenamine 
or  neoarsphenamine  is  also  advisable  on  accoimt  of  its  prophy- 
lactic action,  as  elsewhere  set  forth. 

The  Care  of  Arsphenamine  Needles 

Niceties  in  technic  in  arsphenamine  administration  are  essen- 
tial. Little  matters  of  detail  may  cause  a  change  from  trouble  to 
comfort.  Arsphenamine  needles  need  as  much  care  as  the  other 
parts  of  salvarsan's  administrative  apparatus,  but  they  are  too 
often  neglected.  A  glance  through  the  bore  of  a  used  needle 
will  likely  reveal  a  dirty  lumen  and  the  residue  in  the  bore  when 
examined  will  be  found  to  be  a  black  mass  of  unknown  composi- 
tion, which  has  no  place  in  any  aseptic  operation. 

The  writer  has  kept  needles  clean  by  the  use  of  a  good  metal 
polish  and  a  copper  wire  a  little  larger  than  the  stylet  accompany- 
ing the  needle.  The  wire  should  fit  the  bore  of  the  needle  closely. 
Part  of  the  wire  is  dipped  in  the  metal  polish  and  is  drawn  back 
and  forth  through  the  needle  several  times.  If  the  wire  is  then 
wiped  off  on  a  piece  of  gauze  a  black  deposit  will  be  observed. 

The  clean  wire  is  again  immersed  in  the  metal  polish  and  the 
operation  is  repeated  until  no  deposit  is  left  on  the  gauze.  The 
bore  of  the  needle  should  be  as  clean  as  the  bore  of  a  rifle. 

After  administering  salvarsan  it  is  our  custom  to  boil  the 
needle,  run  alcohol  through  it  and  then  cover  it  with  I  D  L,  an 
Irish  moss  preparation,  which  prevents  rusting.  It  may  also 
be  kept  in  oil. 

Arsphenamine  needles  must  be  very  sharp,  with  a  short  bev- 
elled edge,  to  prevent  wounding  of  the  vein.  We  formerly  sent 
needles  to  an  instrument  maker  to  be  sharpened,  but  of  late  have 
personally  utilized  a  piece  of  carborundum  for  the  purpose.  By 
so  doing  the  physician  can  always  have  a  sharp  needle  at  his 


THE  CURE  OF  SYPHILIS  155 

command,  with  the  kind  of  point  which  his  experience  demon- 
strates is  best. 

In  a  discussion  of  the  care  of  needles,  the  type  of  needle  may  be 
mentioned. 

A  number  of  syphilologists  have  had  special  needles  made 
embodying  ideas  of  their  own,  but  most  physicians  use  the  needle 
they  first  employed  when  giving  intravenous  injections. 

After  trying  the  various  t3^es  on  the  market,  we  have  adopted 
the  Fordyce  and  use  it  exclusively. 

Its  particular  advantage  is  the  shank,  which  enables  the 
operator  to  obtain  such  a  firm  grasp  that  no  sudden  movement 
on  the  part  of  the  patient  can  shake  it  out  of  his  hand. 

This  shank  also  permits  the  physician  to  pursue  a  rolling,  elu- 
sive vein,  which  may  not  have  been  properly  fijced  between  the 
thumb  and  forefinger  of  the  other  hand,  without  making  a  second 
entrance  through  the  skin. 

Hygiene  for  Syphilitic  Patients 

No  alcohoh'c  liquors  should  be  ingested. 

The  use  of  tobacco,  either  by  smoking  or  chewing,  aggravates 
those  cases  in  which  mucous  patches  are  present  in  the  mouth. 

Tepid  baths  should  be  taken  daily,  if  no  eruption  be  present, 
followed  by  a  brisk  rub.  A  hot  bath  should  be  taken  every  two 
or  three  days.  Sometimes  a  hot  water  shower,  followed  by  a  cold 
one,  is  of  benefit.  Turkish  baths  may  be  taken  once  or  twice  a 
week,  if  no  active  skin  troubles  are  present. 

The  teeth  should  be  brushed  in  the  morning,  after  meals,  and 
upon  retiring,  and  a  cleansing  mouth  wash  will  add  to  the 
patient's  comfort. 

The  patient  should  sleep  alone. 

He  should  use  his  own  dishes  and  table  cutlery,  towels,  tooth 
brush,  brushes,  combs,  shaving  utensils,  pencils,  scissors,  etc. 

He  should  kiss  no  one  and  sexual  intercourse  is  strictly  in- 
terdicted for  the  first  year  of  the  disease  or  during  a  relapse. 

During  the  presence  of  oral  mucous  patches  he  should  keep  his 
fingers  out  of  his  mouth  and  be  particular  that  his  saliva  does 
not  come  in  contact  with  any  one  or  with  anything  in  use. 


156  THE  TREATMENT  OF  SYPHILIS 

He  should  wash  his  hands  very  frequently  and  always  after 
touching  his  genitals. 

Dietary  for  Syphilitic  Patients 

In  the  treatment  of  lues  it  should  be  remembered  that  the 
patient  is  suffering  from  a  constitutional  disease,  that  he  demands 
special  food  and  that  his  particular  symptoms  necessitate  treat- 
ment as  they  arise. 

The  following  dietary  is  suggested: 

The  Patient  Can  Have 
Soups,  all  except  tomato. 

Fish. — All  fresh  fish,  boiled,  baked,  or  broiled.  Raw  oysters, 
scallops,  lobsters  and  clams. 

Meat. — Beef,  mutton,  roasted,  boiled  or  broiled;  poultry; 
game;  veal,  lamb  chops  or  cutlets;  eggs,  soft  boiled,  scrambled, 
poached,  raw  or  in  omelettes. 

Farinaceous. — Cracked  wheat,  oatmeal,  mush,  sago,  tapioca, 
rice,  hominy,  barley,  marcaroni,  vermicelli,  whole-wheat  bread, 
stale  or  toasted  wheat  bread,  brown  bread,  milk  toast,  corn 
bread. 

Vegetables. — Green  peas,  string  beans,  parsnips,  turnips, 
spinach,  cauhflower,  mushrooms,  celery,  lettuce,  asparagus, 
sweet  potatoes,  white  potatoes  in  moderation,  preferably  baked. 

Desserts. — Custards,  rice  or  cornstarch  puddings,  blanc  mange. 

Drinks. — ^Water,  plain  or  aerated,  cocoa,  chocolate,  milk,  kou- 
miss. A  limited  amount  of  coffee  may  be  given  when  no  active 
symptoms  are  present. 

The  Patient  Can  Not  Have 

Any  fried  foods,  or  pork  cooked  in  any  way. 

Any  sour,  acid,  spicy  or  peppery  foods. 

Any  canned,  salted,  pickled  or  preserved  meat  or  fish. 

Any  alcohohc  drinks  or  tea. 

Any  pastry. 


THE  CURE   OF  SYPHILIS 


157 


The  patient  should  be  instructed 

To  eat  animal  food  at  every  meal  and  to  eat  more  animal  than 
starchy  food. 

When  Can  the  Syphilitic  Patient  Marry? 

Nearly  forty  years  ago  Fournier  of  Paris,  in  his  Syphilis  et 
Manage,  set  down  these  governing  rules  for  the  marriage  of 
syphilitic  patients : 

a.  Absence  of  actual  specific  lesions. 

b.  Advanced  age  of  the  infection. 

c.  A  certain  period  of  absolute  immunity. 

d.  Non-menacing  character  of  the  disease. 

e.  Sufficient  specific  treatment. 

Finger  of  Vienna  in  1896  specified  that  five  years  should  inter- 
vene between  the  times  of  infection  and  marriage  and  that  three 
years  should  intervene  between  the  last  syphilitic  manifesta- 
tion and  marriage,  there  having  been  systematic  treatment  of  the 
disease,  with  an  energetic  course  of  mercurial  treatment  preceding 
the  marriage  ceremony. 

Dr.  Joseph  Lewi,  who  for  fifty  years  practiced  medicine  in 
Albany,  N.  Y.,  at  a  time  long  before  arsphenamine  was  brought 
to  the  attention  of  the  medical  world,  advised  as  follows : 

"No  man  or  woman  ever  afHicted  with  syphilis  has  a  right  to 
marry  until  three  years  after  all  symptoms  of  the  disease  have 
disappeared.  In  the  meantime  and  for  a  period  of  three  years, 
the  mixed  treatment  (one  thirty-second  of  a  grain  of  corrosive 
sublimate  and  ten  grains  of  iodid  of  potassium)  should  be  given 
such  patients  three  times  a  day  for  a  period  of  twenty  days  at 
four  different  periods  of  each  year." 

Observations,  extending  over  a  period  of  seventy  years,  of 
cases  coming  under  the  care  of  Dr.  Lewi  and  his  sons,  who  co- 
operated with  and  succeeded  him  in  practice,  show  that  where 
the  treatment  was  followed  as  above  outlined,  the  after-effects 
on  progeny  were  limited  to  cases  of  premature  birth  and  of  abor- 
tions in  first  and  second  pregnancies,  and  that  other  compUca- 
tions  were  negligible. 


IS8  THE  TREATMENT  OF  SYPHILIS 

In  the  light  of  our  present  knowledge  the  physician  should  not 
give  his  consent  to  the  marriage  of  a  syphilitic  patient  until  the 
provocative  injection,  after  repeated  Wassermanns,  of  blood  and 
spinal  fluid  have  demonstrated  that  the  spirochetae  have  been 
absolutely  eliminated  from  the  system.  A  man  with  a  positive 
Wassermann,  even  though  it  be  caused  by  an  aortitis  or  a  lesion 
of  the  spinal  cord,  should  not  marry  or  endeavor  to  procreate. 


AUTHORITIES  QUOTED 


Ballanger,  56 

Barewald,  40 

Barnes,  56 

Binz  and  Schulz,  27 

Blue,  98 

Bourrett  and  Fabre,  143 

Brechot,  35 

Bunch,  142 

Burgess,  i 

Cole,  32 
Cotton,  136 
Craig,  60,  107 

Danysz,  103 
Danysz  and  Fleig,  59 
Dinnick,  152 

Ehrlich,  11,  25,  62 
Ellis,  114 

Favre  and  Massia,  73 
Findlay  and  Robertson,  141 
Finger,  157 
Fischer,  57 
Fordyce,  6,  80,  122 
Fournier,  143,  157 

Galliot,  142 
Gennerich,  105 

Harrison,  65 
Harvey,  134 
Herring,  59 
Hewlett,  104 
HiUman,  i 
Hochsinger,  142 


Jackson,  50,  102 
Jacobsen,  93 

Kaliski  and  Strauss,  131 
Keyes,  E.  L.,  Jr.,  56,  loi 

Leduc,  142 
Lewi,  157 
Lisser,  141 
Lydston,  33 

Magian,  34 
Markus,  142 
McCoy,  71,  96 
McNeil,  6 
Morton,  8,  31 
Mouneyrat,  22 
Murray,  41 
Myers,  50,  92 

Nichols,  82 

Ogilvie,  119 
O'Leary,  105 
Ormsby,  36 

PoUitzer,  40 

Rohl  and  Friedberger,  26 
Rothwell,  35 

Sachs,  128 
Sauvage,  143 
Sieburg,  29 
Sinclair,  135 
Smith,  M.  I.,  50,  102 
Smith,  T.  H.,  57 


i6o 

Stevenson,  136 
Stokes,  88,  105 
Swift,  114 

Thomas,  74 
Thompson,  32 
Trimble,  35 


AUTHORITIES  QUOTED 

Vedder,  32,  loi 


Wechselmann,  loi,  146,  153 

White,  151 

Zeissl,  142 


INDEX 


Acute  Optic  Neuritis  and  Salvarsan, 

31 
Administration  of  Mercury,  Technic 

of,  77 
Administration  of  Salvarsan: 
Bringing  out  Veins,  55 
Choice  of  Veins,  52 
Collapse,  Use  of  Tyxamine  in,  104 
Concentrated  Injections,  56 
Danger  of  Rapid  Injections,  55, 96 
Distilled  Water  in,  54 
Epinephrin,  Use  of,  88,  134 
Examination  of  Urine,  31,  52 
Fordyce  Technic,  The,  123 
Helpful  Hints  in,  54 
Into  Superior  Longitudinal  Sinus, 

57 
Intracranial  Injections,  136 
Intraspinal  Treatment,  120 
Introduction  of  Needle,  53 
Necessity  of  Slow  Injections,  S4 
Preparation  of  Patient,  52 
Subarachnoid  Injections,  115 
Swift-Ellis  Method,  114 
Use  of  Vasodilators  in,  56 
"Windows"  over  Vein,  56 

Amboceptor,  2 

Ammonium  lodid,  10 

Antenatal  Treatment,  142 

Antibodies,  3 

Antigens,  3 

Antiluetic  Agents,  10 

Antiluetic  Treatment,  Plan  for,  37 

Antiphlogistine  after  Intramuscular 
Treatment,  66 

Arsacetin,  11,  21,  26 


Arsenic,  10 

Arsenic  Compoimds,  Chemotherapy 

of,  25 
Arteries  as  Carriers  of  Therapeutic 

Agents,  13s 
Arsphenamine: 

Accidents  following  Use  of,  100 
After  Treatment  following  Intra- 
muscular Use,  66 
Alkalinization,  Importance  of,  46, 

SO 
Arsenic  Content  of,  19 
As  an  Abortive  Agent,  30 
As  a  Prophylactic,  34 
Apparatus  for  Administration,  43 
Blood  Pressure  During  Adminis- 
tration, 102 
Chemistry  of,  1 1 
Color  and  Solubility,  19 
Comparative    Use    with    Neoar- 

sphenamine,  35 
Concentration  of,  46,  56,  96 
Contraindications  to,  30,  133 
Diagrammatic  Outline  of,  16 
Dilution  of,  47,  95 
Discovery  of,  12 

Distilled  Water  for  Solution,  44 
Dosage,  37,  85 
Effects  of  Wassermann  Reaction 

on,  106 
History  of,  11 
Immediate  Mother  Substance  of, 

14 
In  Non-leutic  Conditions,  34 
Indications  for,  30 
Intramuscular  Administration,  59, 

62 
Intravenous   Administration,    42 


l62 


INDEX 


Intravenous  vs.  Intraspinous  med- 
ication, 128 
Manufacture  of,  19 
Needles,  Care  of,  154 
Other  Derivatives  of,  22 
Preparation  for  Intramuscular 

Use,  62 
Preparation  of,  13 
Preparation  of  Solution  of,  42 
Precursors  of,  21 
Rapidity  of  Injection,  96 
Rectal  Administration,  67 
Serological  Effects  of,  107 
Sodium  Salt  of,  21 
Technic  of  Administration,  42 
Temperature  of  Solution,  47 
Therapeutic  Effects  of,  31 
Therapeutic  Efl&ciency,  32 
Use  Following  Acute  Diseases,  31 
Use  on  Aged  Persons,  31 
Variations  in  Different  Brands  of, 

19 
Asiphyl,  II 
Atoxyl,  II,  21,  26 

B 

Blood  Precipitates,  59 


Complement  Fixation,  4 

Concentrated  Neosalvarsan  Injec- 
tion, 70 

Concentrated  Salvarsan  Injections, 
S6 

Congenital  Syphilis,  139 

D 

Diabetes  and  Arsphenamine,  30 
Dietary  for  Syphilitic  Patients,  156 
Dilute  Neosalvarsan  Injection,  72 
Distilling  Apparatus,  45 
Distilled  Water  in  Administration  of 
Arsenicals,  44 

E 

Early  Meningitis,  116 

Effects  of  Arsphenamine  and  Mer- 
cury on  Wassermann  Reaction, 
106 

Embolism  Following  Arsphenamine, 
100 

Epifascial  Neosalvarsan  Injections, 
140 

F 

Filaria  and  Arsphenamine,  34 
Frambesia  and  Arsphenamine,  34 


Calomel-Neosalvarsan  in  Congenital 
Syphilis,  139 

Central  Nervous  System,  Treat- 
ment of  Syphilis  of,  114 

Chancre,  Excision  of,  37 

Chemotherapy  of  Arsenic  Com- 
pounds, 25 

Choroiditis  and  Salvarsan,  31 

"Cobble  Stone"  Buttocks,  80 

Cod  Liver  Oil  in  Syphilis,  86 

Collapse,  Use  of  Tyramine  in,  104 

Collapsules,  38,  81 

Colloidal  Gold  Test,  6 

Complement  (Alexine),  i 


Galyl,  22 

Gold  Curve,  117 

H 

Hectine,  11 

Hygiene  for  Sj^hilitic  Patients,  155 


Infection  of  Physicians  with  Syphi- 
lis, 153 

Infiltration  Following  Arsphena- 
mine, 100 


INDEX 


163 


Intensive  Salvarsan  Treatment,  40, 

127,  131 
Interstitial  Keratitis  and  Salvarsan, 

31 
Iodides,  10,  82,  86,  142,  147,  148 

Effectiveness  of  Heavy  Doses,  84 

In  Tertiary  and  Latent  Cases,  39 

lodism,  84 

Methods  of  Emplojmient,  82 
Iron  in  Syphilis,  86,  148 
Inunctions  of  Mercury,  78,  146 


Lange's  Colloidal  Gold  Test,  6 
Luargol,  22 
Ludyl,  22 
Luetic  Curve,  7 
Luetic  Meningitis,  136 
Luetin  Test,  144 

M 

Malaria  and  Arsphenamine,  34 
Marriage  of  the  Syphilitic,  157 
Marsh  Fever  and  Arsphenamine,  34 
Massage  Following  Mercury  Injec- 
tion, 78 
Mercury,  10,  77,  106,  107,  112,  131, 
139,  142,  146,  149,  157 
Administration  by  Mouth,  79 
Administration,  Technic  of,  77 
Advantages    and    Disadvantages 

of  Soluble  Forms,  81 
Anatomical  Sites  for  Immctions, 

79 
Benzoate,  10,  134 
Bichlorid,  10,  38,  80,  85,  131,  146, 

147,  IS7 
Biniodid,  10,  147 
Blue  Mass,  10 
Calomel,  10,  139,  146 
Collapsules,  38,  81 
Form  to  be  Used,  80 
Fimiigation,  79 


Gray  Oil,  10,  80 

Inhalation,  79 

Intramuscular  Injection,  77 

Intravenous  Method,  80 

Inunctions,  78,  146 

Mercury  with  Chalk,  10,  146 

Not  a  Staple  Curative  Agent,  112 

Oleate,  10 

Protiodid,  10,  147 

Salicylate,  10,  38,  80,  86, 131, 134, 
149 

Serological  Effects  of,  107 

Succinimid,  10,  80 

Unguentum  hydrargyri,  10,  78 
Methods  of  Preparing  Intramuscu- 
lar Injections  of  Salvarsan 

Alt,  64 

American,  66 

British  Army,  65 

EhrUch,  62 

Michaelis,  64 

Oily  Emulsions,  64 
Mixed  Treatment,  147,  157 
Myocarditis  and  Arsphenamine,  30 

N 

Neoarsphenamine : 

Administration,  Technic  of,  69 
Apparatus  for  Injection,  73 
Concentrated  Intravenous  Admin- 
istration, 70 
Concentrated    Method,    Technic 

of,  73 

Dilute  Intravenous  Administra- 
tion, 69 

Dosage,  37,  85 

Evolution  of,  20 

Gravity  Method,  72 

Overconcentration,  Dangers  of,  72 

Preparation  of  Solution,  69 

Subcutaneous  Method,  Technic 
of,  74 

Time  Necessary  for  Injection,  71 


164 


INDEX 


Nephritis  and  Arsphenamine,  30 

Neosalvarsan: 

Administration,  Technic  of,  69 
Apparatus  for  Injection,  73 
Comparative  Use  with  Salvarsan, 

35 

Concentrated    Intravenous    Ad- 
ministration, 70 

Concentrated    Method,    Technic 

of,  73 
Congenital  SyphiHs,  139 
Courses  of  Treatment,  87 
Dilute   Intravenous   Administra- 
tion, 69 
Dosage,  37,  85 

Epifascial  Injections,  140,  146 
Gravity  Method,  72 
Intra      Arterial      Injection      in 

Cerebro-Spinal  SyphUis,  135 
Jugular  Vein,  Injections  in,  140, 

144 
Overconcentration,  Dangers  of,  72 
Preparation  of  Solutions,  69 
Sinus   Longitudinalis,    Injections 

in,  140 
Structural  Formulas  of,  28 
Subcutaneous   Method,    Technic 

of,  74 
Swift-Ellis  Method,  114 
Time  Necessary  for  Injection,  71 
Wide    Field    for    in    Congenital 
Syphilis,  145 
"914,"  22 

Nitroglycerin  in  Arsphenamine  Ad- 
ministration, 56 
Noguchi's  Modification,  5 
Nux  Vomica  in  SyphUis,  87 

O 

Ogilvie's  Modification,  119 
Optic  Atrophy  and  Salvarsan,  125 
Organic  Disease  and  Arsphenamine, 
31 


Paralytica  Dementia,  117 

Paresis,  136,  137 

Paretic  Curve,  7 

Pentavalent    Arsenic    Compounds, 

25,  86,  142 
Persistent    Positive    Reaction    and 

a  Spirochetal  Focus,  121 
Phlebitis   following  Arsphenamine, 

100 
Positive  Results  from  Salvarsan  and 

Mercury,  108 
Potassimn  lodid,  10, 39,  83, 147, 148, 

157 

Potassiiun  Permanganate  in  Mahg- 
nant  Syphilis,  148 

Potency  of  Trivalent  Arsenic,  29 

Pregnant  Women,  Antiluetic  Treat- 
ment of,  141 

Preparation  of  Patient  for  Sal- 
varsan, 52 

Pre-paresis,  125,  137 

Provocative  Wassermanns,  39,  105 

Pyorrhea  and  Arsphenamine,  34 


Q 

Qviinin  in  Malignant  SyphiHs,  148 

R 

Reactions  and  Accidents: 
Accidents,  100 
Atropin  in,  88 
Causes  of,  93 
Death,  Causes  of,  103 
Effects    of    disturbance    of    pul- 
monary circulation,  103 
Epinephrin  in,  88,  134 
From  Faulty  Technic,  91 
Herxheimer  Reaction,  92,  124 
Kidneys,  Necessity  of  Watching, 

lOI 

Nerve  Disturbances,  92 


INDEX 


165 


Nitroid  Crises,  88 
Revelations  from  Animal  Experi- 
ments, lOI 
Some  Late  Reactions,  91 
Tyramine  in  Cases  of  Collapse, 

lOI 

Recurrent  fever  and  Arsphenanaine, 

34 
Reinfection,  Syphilitic,  150 
Ricord's  K.  I.  Formula,  83 


Salvarsan : 

Accidents  Following  Use  of,  100 

Action  on  Spirochetae  Pallidae,  39 

Advantages  of  in  Congenital 
Syphilis,  143 

Alkalinization,  Importance  of,  46, 
50,  120 

And  Mercury,  40. 

Apparatus  for,  43 

Chemical  Transformation  of,  49 

Clinical  Value  of,  32 

Comparative  Use  with  Neosal- 
varsan,  35 

Concentration  of,  46,  56 

Contraindications,  30,  133 

Courses  of  Treatment,  86 

Danger  of  Too  Concentrated 
Solution,  57,  96 

Dilution  of,  47,  95 

Discovery  of,  12 

Distilled  Water  for,  44 

Dosage  of,  37,  85 

Effects  on  Wassermann  Reaction, 
106 

Efficiency  of,  32 

Filtering  of  Solution,  51 

History  and  Chemistry  of,  11 

Indications  for  Use,  33 

Injection  into  Superior  Longi- 
tudinal Sinus,  57 

In  Luetic  Meningitis,  136 


In  Malignant  S)TDhilis,  31,  148 
In  Paresis,  136,  137 
In  Pre-paresis,  125,  137 
Intensive  Treatment,  40,  127, 131 
In  Tabes,  31,  117,  136,  137 
In  Tertiary  Lesions  of  Viscera,  148 
Intracranial  Method,  136 
Intramuscular  Administration,  59, 

62 
Intraspinal  Treatment,  120 
OgUvie's  Modification,  119 
PermeabUity  of  Meninges  to  Ar- 
senic, 137 
Pregnancy,  Treatment  during,  141 
Preparation  of  Solution,  42 
Rectal  Administration,  67 
Serological  Effects  of,  107 
Sodium  Hydroxide,  Use  of,  48 
Structural  Formulas  of,  28 
Subarachnoid  Injections,  115 
Swift-Ellis  Method,  114 
Technic  of  Administration,  42 
Temperature  of  Solution,  47 
Value  of  Large  Production  of,  19 

Septicemia  and  Neoarsphenamine,  3  5 

"606,"  22 

Soamin,  26 

Sodium  Cacodylate,  26 

Sodimn  lodid,  10 

Spirarsyl,  22 

Spirochetae  not  Affected  by  lodin,  82 

Strontium  lodid,  10 

Strychnin  in  Sj^hilis,  86 

Subcutaneous  Injection  of  Neosal- 
varsan,  74 

S)^hnitic  Reinfection,  150 

S3^hiHs: 
Abortion  of,  38 
Antenatal  Treatment,  142 
Arsphenamine  (Salvarsan),  Treat- 
ment by,  42 
Central  Nervous  System,  Treat- 
ment of  Syphilis  of,  1 14 
Congenital,  139 


i66 


INDEX 


Cure  of,  150 

Dietary  for  Syphilitic  Patients, 
156 

Dosage  of  Salvarsan  and  Neosal- 
varsan,  37 

Epifascial  Neosalvarsan  Injec- 
tions in  Congenital  Syphilis, 
139,  146 

Fordyce  Technic,  The,  123 

General  Treatment,  86 

Hydrotherapeutic  Treatment,  87 

Hygiene  for  Patients,  155 

Intensive  Treatment,  40,  127,  131 

Intracranial  Method  of  Treat- 
ment, 136 

Intraspinal  Treatment,  120 

Iodides  in  Tertiary  and  Latent 
Cases,  39 

MaUgnant  SyphiUs,  Treatment 
of,  148 

Mercurials  and  Iodides  in,  77 

Necessity  of  Locating  Focus  of 
Infection,  123 

Necessity  of  Prompt  Treatment, 

37 
Neoarsphenamine  (Neosalvarsan), 

Treatment  by,  69 
Neosalvarsan   Intra-arterially   in 

Cerebrospinal  Lues,  135 
Plan  of  Treatment  for,  37 
Pregnancy,  Treatment  during,  141 
Prevention  of  Infection,  153 
Provocative  Wassermann  in,  105 
Resume  of  Treatment,  85 
Salvarsan  and  Mercury  Necessary 

in,  40 
Standard  of  Cure  of,  152 
Subarachnoid  Injections,  115 
Swift-Ellis  Method,  114 
S)T)hilitic    Aortitis,    Endarteritis 

and  Periarteritis,  148 
Tertiary  Lesions  of  Viscera,  148 
Treatment    of    Long    Standing 

Cases,  38 


Treatment  of  Primary  and  Sec- 
ondary Cases,  38 

Turkish  Baths  During  Treat- 
ment, 87 

Visceral  SyphiUs,  Treatment  of, 
148 

Wassermann  Reaction  following 
Treatment,  39. 


Tabes  Dorsahs,  117,  136,  137 
Technic  of  Salvarsan  Injection,  42 
Thrombus  following  Arsphenamine, 

100 
Tick  Fever  and  Arsphenamine,  34 
Trench  Mouth  and  Arsphenamine, 

34 
Trivalent  Arsenic  Compoimds,  28 
Tuberculosis  and  Arsphenamine,  30 
Tyramine  in  Cases  of  Collapse,  104 

U 

U.  S.  Public  Health  Service's  In- 
structions on  Arsenicals,  98 

Urine,  Examination  of,  After  In- 
jection, 31,  52 


Vein,  Choice  of,  52 

Vincent's  Angina  and  Arsphena- 
mine, 34 

Visceral  Syphilis,  Salvarsan  in,  148 

Vision,  Intraspinal  Treatment  in 
Preservation  of,  124 

W 

Wassermann  Reaction,  i 

After   Salvarsan-Mercury  Treat- 
ment, 39 
Clinical  Application  of,  8 
Effects    of    Arsphenamine    and 
Mercury  on,  106 


INDEX 


167 


Indications  for  Provocative,  105 
Negative  Reactions,  Significance 

of,  9 
Of  Spinal  Fluid,  39 
Positive    Reactions,    Significance 

of,  8 
Positive  Results  from  Salvarsan 

and  Mercury,  108 


Provocative,  39,  105 
Reaction  in  Latent  Cases,  9 
Value  in  Differential  Diagnosis, 

8 
Value  in  Standard  of  Cure,  152 
When  Can  the  Sj^hilitic  Patient 

Marry?  157 


Printed  in  the  United  States  of  America 


RC201 
Baketel 


B17 


':i^f       ^d 


